Monoacylglycerol lipase modulators

ABSTRACT

3.1.0 and 4.1.0 Azabicycle compounds of Formula (I), pharmaceutical compositions containing them, methods of making them, and methods of using them including methods for treating disease states, disorders, and conditions associated with MGL modulation, such as those associated with pain, psychiatric disorders, neurological disorders (including, but not limited to major depressive disorder, treatment resistant depression, anxious depression, bipolar disorder), cancers and eye conditions.wherein X, Y, R1, R2a, and R2b are defined herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Patent Application No.62/972,484, filed on Feb. 10, 2020, which is incorporated herein in itsentirety.

FIELD OF THE INVENTION

The present invention is related to certain 3.1.0 and 4.1.0 azabicyclechemical entities having MGL modulating properties, pharmaceuticalcompositions comprising these chemical entities, chemical processes forpreparing these chemical entities and their use in the treatment ofdiseases, disorders or conditions associated with MGL receptor activityin subjects, in particular humans.

BACKGROUND OF THE INVENTION

Cannabis Sativa and analogs of Δ⁹-tetrahydrocannabinol have been usedsince the days of folk medicine for therapeutic purposes. Theendocannabinoid system consists of two G-protein coupled receptors,cannabinoid receptor type 1 (CB1) (Matsuda et al., Nature, 1990, 346,561-4) and cannabinoid receptor type 2 (CB2) (Munro et al., Nature,1993, 365, 61-5). CB1 receptor is one of the most abundant G-proteincoupled receptor expressed in the brain (Herkenam et al., Proc. Nat.Acad. Sci., 1990, 87 (5), 1932-1936). CB1 is also expressed peripherallyin the liver, gastrointestinal tract, pancreas, adipose tissue, andskeletal muscles (Di Marzo et al., Curr Opin Lipidol, 2007, 18,129-140). CB2 is predominantly expressed in immune cells such asmonocytes (Pacher et al., Amer J Physiol, 2008, 294, H1133-H1134) andunder certain conditions (inflammation) in the brain ((Benito et al.,Brit J Pharmacol, 2008, 153, 277-285) and in skeletal (Cavuoto et al.,Biochem Biophys Res Commun, 2007, 364, 105-110) and cardiac muscles(Hajrasouliha et al., Eur J Pharmacol, 2008, 579, 246-252).

In 1992, N-arachidonoylethanolamine (AEA or anandamide) was found to bean endogenous ligand for cannabinoid receptors (Devane et al., Science,1992, 258, 1946-9). Subsequently, 2-arachidonoylglycerol (2-AG) was alsoidentified as an additional endogenous ligand for the cannabinoidreceptors (Mechoulam et al., Biochem Pharmacol, 1995, 50, 83-90; Sugiuraet al., Biochem Biophys Res Commun, 1995, 215, 89-97). Concentrations of2-AG were reported to be at least 100 times higher than these ofanandamide in the rat brain (Buczynski and Parsons, Brit J Pharmacol,2010, 160 (3), 423-42). Therefore 2-AG may play more essentialphysiological roles than anandamide in the brain endocannabinoid system(Sugiura et al. Prostaglandins Leukot Essent Fatty Acids., 2002,February-March, 66(2-3):173-92). The endocannabinoid 2-AG is a fullagonist for CB1 and CB2 receptors, while anandamide is a partial agonistfor both receptors (Suguira et al., Prog Lipid Res, 2006, 45(5):405-46).Unlike many classical neurotransmitters, endocannabinoids signal througha retrograde mechanism. They are synthesized on demand in postsynapticneurons and then rapidly degraded following binding to presynapticcannabinoid receptors (Ahn et al., Chem Rev. 2008, 108(5):1687-707).Monoacylglycerol lipase (MGLL, also known as MAG lipase and MGL) is theserine hydrolase responsible for the degradation of 2-AG intoarachidonic acid and glycerol in the central nervous system (Mechoulamet al., Biochem Pharmacol, 1995, 50, 83-90; Sugiura et al., BiochemBiophys Res Commun, 1995, 215, 89-97; Long et al., Nat Chem Biol. 2009January; 5(1):37-44), Schlosburg et al, Nat Neurosci., 2010, September;13(9):1113-9) and peripheral tissues (Long et al., Chem Biol., 2009 Jul.31; 16(7):744-53). Anandamide is hydrolyzed by fatty acid amidehydrolase (FAAH) (Piomelli, Nat Rev Neurosci, 2003, 4, 873-884). MGLexists in both soluble and membrane bound forms (Dinh et al., Proc NatlAcad Sci USA., 2002, Aug. 6; 99(16):10819-24). In the brain MGL islocated in presynaptic neurons (Straiker et al., Mot Pharmacol., 2009,December; 76(6):1220-7) and astrocytes (Walter et al., J Neurosci.,2004, Sep. 15; 24(37):8068-74) within regions associated with high CB1receptor density. Compared to wild-type controls, genetic ablation ofMGL expression produces 10-fold increase in brain 2-AG levels withoutaffecting anandamide concentration (Schlosburg et al., Nat Neurosci.,2010, September; 13(9):1113-9).

Thus, MGL modulation offers an interesting strategy for potentiating thecannabinoid system. The primary advantage of this approach is that onlybrain regions where endocannabinoids are actively produced will bemodulated, potentially minimizing the side effects associated withexogenous CB1 agonists. Pharmacological inactivation of MGL by covalentinhibitors in animals increase 2-AG content in brain and peripheraltissues and has been found to produce antinociceptive, anxiolytic andanti-inflammatory effects that are dependent on CB1 and/or CB2 receptors(Long et al., Nat Chem Biol., 2009, Jan., 5(1):37-44; Ghosh et al., LifeSci., 2013, Mar. 19, 92(8-9):498-505; Bedse et al., Biol Psychiatry.,2017, Oct. 1, 82(7):488-499; Bernal-Chico et al., Glia., 2015, January,63(1):163-76; Patel et al. Neurosci Biobehav Rev., 2017, May, 76(PtA):56-66; Betse et al., Transl Psychiatry., 2018, Apr. 26, 8(1):92). Inaddition to the role of MGL in terminating 2-AG signaling, MGLmodulation, including MGL inhibition also promotes CB1/2-independenteffects on neuroinflammation (Nomura et al., Science., 2011, November11; 334(6057):809-13). MGL modulation, including MGL inhibition leads toreduction in proinflammatory prostanoid signaling in animal models oftraumatic brain injury (Katz et al., J Neurotrauma., 2015, March 1;32(5):297-306; Zhang et al., J Cereb Blood Flow Metab., 2015, March 31;35(4):443-453), neurodegeneration including Alzheimer's disease (Piro etal., Cell Rep., 2012, Jun. 28, 1(6):617-23; Wenzel et al., Life Sci.,2018, Aug. 15, 207:314-322; Chen et al., Cell Rep., 2012, Nov. 29,2(5):1329-39), Parkinson's disease (Nomura et al., Science, 2011, Nov.11, 334(6057), 809-13; Pasquarelli et al., Neurochem Int., 2017,November, 110:14-24), amyotrophic lateral sclerosis (Pasquarelli et al.,Neuropharmacology, 2017, Sep. 15, 124:157-169), multiple sclerosis(Hernadez-Torres et al., Angew Chem Int Ed Engl., 2014, Dec. 8,53(50):13765-70; Bernal-Chico et al., Glia., 2015, January,63(1):163-76), Huntington's disease (Covey et al.,Neuropsychopharmacology, 2018, 43, 2056-2063), Tourette syndrome andstatus epilepticus (Terrone et al., Epilepsia., 2018, January, 59(1),79-91; von Ruden et al., Neurobiol Dis., 2015, May; 77:238-45).

Therefore, by potentiating the cannabinoid system and attenuatingproinflammatory cascades, MGL modulation, including MGL inhibitionoffers a compelling therapeutic approach for the treatment of a vastarray of complex diseases. Importantly, MGL modulation, including MGLinhibition in animals does not produces the full spectrum ofneurobehavioral effects observed with Δ⁹-tetrahydrocannabinol and otherCB1 agonists (Tuo et al., J Med Chem., 2017, Jan. 12, 60(1), 4-46;Mulvihill et al., Life Sci., 2013, Mar. 19, 92(8-9), 492-7).

Endocannabinoid hypoactivity is a risk factor for the treatment ofdepression, anxiety, and post-traumatic stress disorders. Millennia ofhuman use of Cannabis sativa, and a brief period in which humans weretreated with the endocannabinoid antagonist, rimonabant, provide supportfor that hypothesis. 2-AG levels are decreased in individuals with majordepression (Hill et al., Pharmacopsychiatry., 2008, March; 41(2): 48-53;Hill et al., Psychoneuroendocrinology., 2009, September; 34(8):1257-1262). Low circulating 2-AG levels predict rates of depression(Hauer et al., Rev Neurosci., 2012, 23(5-6):681-90). Reduced circulating2-AG has been found in patient with post-traumatic stress disorder(PTSD) (Hill et al., Psychoneuroendocrinology, 2013, 38 (12),2952-2961). Healthy volunteers exposed to chronic stressors exhibitedprogressively diminished circulating 2-AG levels which correlated withthe onset of reductions in measures of positive emotions (Yi et al.,Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2016, 67(3), 92-97). The CB1 receptor inverse agonist/antagonist Rimonabant hasbeen withdrawn from the market due to the high incidence of severedepression and suicidal ideation (Christensen et al., The Lancet, 2007,370, 1706-1713). Therefore, MGL modulators are potentially useful forthe treatment of mood disorders, anxiety, and PTSD.

Cannabinoid receptor agonists are clinically used to treat pain,spasticity, emesis and anorexia (Di Marzo, et al., Annu Rev Med., 2006,57:553-74; Ligresti et al., Curr Opin Chem Biol., 2009, June;13(3):321-31). Therefore, MGL modulators, including MGL inhibitors arealso potentially useful for these indications. MGL exerts CB1-dependantantinociceptive effects in animal models of noxious chemical,inflammatory, thermal and neuropathic pain (Guindon et al., Br JPharmacol., 2011, August; 163(7):1464-78; Kinsey et al., J Pharmacol ExpTher., 2009, September; 330(3):902-10; Long et al., Nat Chem Biol.,2009, January; 5(1):37-44). MGL blockade reduces mechanical and acetoneinduced cold allodynia in mice subjected to chronic constriction injuryof the sciatic nerve (Kinsey et al., J Pharmacol Exp Ther., 2009,September; 330(3):902-10). MGL inhibition produces opiate-sparing eventswith diminished tolerance, constipation, and cannabimimetic side effects(Wilkerson et al., J Pharmacol Exp Ther., 2016, April; 357(1):145-56).MGL blockade is protective in model of inflammatory bowel disease(Alhouayek et al., FASEB J., 2011, August; 25(8):2711-21). MGLinhibition also reverse Paclitaxel-induced nociceptive behavior andproinflammatory markers in a mouse model of chemotherapy-inducedneuropathy (Curry et al., J Pharmacol Exp Ther., 2018, July;366(1):169-18). MGL inhibitors are also potentially useful for thetreatment of chronic inflammatory condition of the urinary bladder likeinterstitial cystitis (Chinnadurai et al., 2019, October; 131: 109321).

Inhibition of 2-AG hydrolysis exerts anti-proliferative activity andreduction in prostate cancer cell invasiveness (Nithipatikom et al.,Cancer Res., 2004, Dec. 15, 64(24):8826-30; Nithipatikom et al., BiochemBiophys Res Commun., 2005, July 15,332(4):1028-33; Nithipatikom et al.,Prostaglandins Other Lipid Mediat., 2011, February, 94(1-2):34-43). MGLis upregulated in aggressive human cancer cells and primary tumors whereit has a unique role of providing lipolytic sources of free fatty acidsfor synthesis of oncogenic signaling lipids that promote canceraggressiveness. Thus, beyond the physiological roles of MGL in mediatedendocannabinoid signaling, MGL in cancer plays a distinct role inmodulating the fatty acid precursor pools for synthesis ofprotumorigenic signaling lipids in malignant human cancer cells.

MGL blockade shows anti-emetic and anti-nausea effects in a lithiumchloride model of vomiting in shrews (Sticht et al., Br J Pharmacol.,2012, April, 165(8):2425-35). MGL modulators, including MGL inhibitorsmay have utility in modulating drug dependence of opiates. MGL blockadereduces the intensity of naloxone-precipitated morphine withdrawalsymptoms in mice. MGL blockade also attenuated spontaneous withdrawalsigns in morphine-dependent mice (Ramesh et al., J Pharmacol Exp Ther.,2011, October, 339(1):173-85).

MGL modulators are also potentially useful for the treatment of eyeconditions, including but not limited to, glaucoma and disease statesarising from elevated intraocular pressure (Miller et al.,Pharmaceuticals, 2018, 11, 50).

SUMMARY OF THE INVENTION

Embodiments of the present invention relate to chemical entities,pharmaceutical compositions containing them, methods of making andpurifying them, and methods for using them the treatment of diseases,disorders, and conditions associated with the MGL modulation. Anadditional embodiment of the invention is a method of treating a subjectsuffering from or diagnosed with a disease, disorder, or conditionassociated with the MGL modulation using at least one chemical entity ofthe invention.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

Embodiments of this invention are compounds of Formula (I),

wherein

X is CH₂ or O;

Y is selected from the group consisting of:

R¹ is H;

R^(2a) and R^(2b) are each independently H;

R³ is selected from the group consisting of: 2,3-dihydro-1H-indene;pyridyl substituted with C₁₋₆alkyl; phenyl; and phenyl substituted withone or two members each independently selected from the group consistingof: halo, C₁₋₆alkyl, C₁₋₆alkyl substituted with OH, C₁₋₆alkylsubstituted with CO₂H, C₁₋₆haloalkyl, OC₁₋₆haloalkyl, C₃₋₆cycloalkyl,O-phenyl, and C₃₋₆cycloalkyl substituted with CH₃;

R^(a) and R^(b) are each independently selected from the groupconsisting of: H and halo; and R^(c) is H or CH₃;

and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the terms “including”, “containing” and “comprising” areused in their open, non-limiting sense.

Unless qualified specifically in particular instances of use, the term“alkyl” refers to a straight- or branched-chain alkyl group having from1 to 8 carbon atoms in the chain. Examples of alkyl groups includemethyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl,isohexyl, and groups that in light of the ordinary skill in the art andthe teachings provided herein would be considered equivalent to any oneof the foregoing examples. “C₁₋₆alkyl” refers to straight- orbranched-chain alkyl group having from 1 to 6 carbon atoms in the chain.“C₁₋₄alkyl” refers to straight- or branched-chain alkyl group havingfrom 1 to 4 carbon atoms in the chain.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkylgroups include the following entities, in the form of properly bondedmoieties:

The term “3.1.0 azabicycle” refers to a bicyclic bridged compounds thatcontain a nitrogen. Illustrative example of 3.1.0 azabicycle groupinclude the following entities, in the form of properly bonded moieties:

The term “4.1.0 azabicycle” refers to a bicyclic bridged compounds thatcontain a nitrogen. Illustrative example of 4.1.0 azabicycle groupsinclude the following entities, in the form of properly bonded moieties:

The term “halogen” or “halo” represents chlorine, fluorine, bromine, oriodine.

The term “haloalkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 6 carbon atoms in the chain optionally substitutinghydrogens with halogens. The term “C₁₋₄ haloalkyl” as used here refersto a straight- or branched-chain alkyl group having from 1 to 4 carbonatoms in the chain, optionally substituting hydrogens with halogens.Examples of “haloalkyl” groups include trifluoromethyl (CF₃),difluoromethyl (CF₂H), monofluoromethyl (CH₂F), pentafluoroethyl(CF₂CF₃), tetrafluoroethyl (CHFCF₃), monofluoroethyl (CH₂CH₂F),trifluoroethyl (CH₂CF₃), tetrafluorotrifluoromethylethyl (CF(CF₃)₂), andgroups that in light of the ordinary skill in the art and the teachingsprovided herein would be considered equivalent to any one of theforegoing examples.

The term “aryl” refers to a monocyclic, aromatic carbocycle (ringstructure having ring atoms that are all carbon) having 6 atoms per ring(Carbon atoms in the aryl groups are sp2 hybridized.)

The term “phenyl” represents the following moiety:

Those skilled in the art will recognize that the species of 3.1.0azabicycle, 4.1.0 azabicycle, cycloalkyl or aryl groups listed orillustrated above are not exhaustive, and that additional species withinthe scope of these defined terms may also be selected.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system.

The term “variable point of attachment” means that a group is allowed tobe attached at more than one alternative position in a structure. Theattachment will always replace a hydrogen atom on one of the ring atoms.In other words, all permutations of bonding are represented by thesingle diagram, as shown in the illustrations below.

Those skilled in the art will recognize that that if more than one suchsubstituent is present for a given ring, the bonding of each substituentis independent of all of the others. The groups listed or illustratedabove are not exhaustive.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of such formula. The compounds of this invention maypossess one or more asymmetric centers; such compounds can therefore beproduced as individual (R)- or (S)-stereoisomers or as mixtures thereof.Thus, any formula given herein is intended to represent a racemate, oneor more of its enantiomeric forms, one or more of its diastereomericforms, and mixtures thereof. Additionally, any formula given herein isintended to refer also to any one of: hydrates, solvates, polymorphs andof such compounds, and mixtures thereof, even if such forms are notlisted explicitly.

The term “R” at a stereocenter designates that the stereocenter ispurely of the R-configuration as defined in the art; likewise, the term“S” means that the stereocenter is purely of the S-configuration. Asused herein, the term “RS” refers to a stereocenter that exists as amixture of the R- and S-configurations.

Compounds containing one stereocenter drawn without a stereo bonddesignation are a mixture of 2 enantiomers. Compounds containing 2stereocenters both drawn without stereo bond designations are a mixtureof 4 diastereomers. Compounds with 2 stereocenters both labeled “RS” anddrawn with stereo bond designations are a 2-component mixture withrelative stereochemistry as drawn. Unlabeled stereocenters drawn withoutstereo bond designations are a mixture of the R- and S-configurations.For unlabeled stereocenters drawn with stereo bond designations, theabsolute stereochemistry is as depicted.

Reference to a compound herein stands for a reference to any one of: (a)the actually recited form of such compound, and (b) any of the forms ofsuch compound in the medium in which the compound is being consideredwhen named. For example, reference herein to a compound such as R—COOH,encompasses reference to any one of: for example, R—COOH(s),R—COOH(sol), and R—COO-(sol). In this example, R—COOH(s) refers to thesolid compound, as it could be for example in a tablet or some othersolid pharmaceutical composition or preparation; R—COOH(sol) refers tothe undissociated form of the compound in a solvent; and R—COO-(sol)refers to the dissociated form of the compound in a solvent, such as thedissociated form of the compound in an aqueous environment, whether suchdissociated form derives from R—COOH, from a salt thereof, or from anyother entity that yields R—COO— upon dissociation in the medium beingconsidered. In another example, an expression such as “exposing anentity to compound of formula R—COOH” refers to the exposure of suchentity to the form, or forms, of the compound R—COOH that exists, orexist, in the medium in which such exposure takes place. In stillanother example, an expression such as “reacting an entity with acompound of formula R—COOH” refers to the reacting of (a) such entity inthe chemically relevant form, or forms, of such entity that exists, orexist, in the medium in which such reacting takes place, with (b) thechemically relevant form, or forms, of the compound R—COOH that exists,or exist, in the medium in which such reacting takes place. In thisregard, if such entity is for example in an aqueous environment, it isunderstood that the compound R—COOH is in such same medium, andtherefore the entity is being exposed to species such as R—COOH(aq)and/or R—COO-(aq), where the subscript “(aq)” stands for “aqueous”according to its conventional meaning in chemistry and biochemistry. Acarboxylic acid functional group has been chosen in these nomenclatureexamples; this choice is not intended, however, as a limitation but itis merely an illustration. It is understood that analogous examples canbe provided in terms of other functional groups, including but notlimited to hydroxyl, basic nitrogen members, such as those in amines,and any other group that interacts or transforms according to knownmanners in the medium that contains the compound. Such interactions andtransformations include, but are not limited to, dissociation,association, tautomerism, solvolysis, including hydrolysis, solvation,including hydration, protonation, and deprotonation. No further examplesin this regard are provided herein because these interactions andtransformations in a given medium are known by any one of ordinary skillin the art.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number in an enriched form. Examples of isotopesthat can be incorporated into compounds of the invention in a form thatexceeds natural abundances include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as²H (or chemical symbol D), ³H (or chemical symbol T), ¹¹C, ¹³C, ¹⁴C,¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ³⁶Cl, and ¹²⁵I, respectively. Suchisotopically labelled compounds are useful in metabolic studies(preferably with ¹⁴C), reaction kinetic studies (with, for example ²H or³H), detection or imaging techniques [such as positron emissiontomography (PET) or single-photon emission computed tomography (SPECT)]including drug or substrate tissue distribution assays, or inradioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeledcompound may be particularly preferred for PET or SPECT studies.Further, substitution with heavier isotopes such as deuterium (i.e., ²H,or D) may afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements. Isotopically labeled compounds of this inventioncan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forsuch variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of the species for the same variableelsewhere in the formula, unless stated otherwise.

The term C_(n-m) alkyl refers to an aliphatic chain, whether straight orbranched, with a total number N of carbon members in the chain thatsatisfies n≤N≤m, withm>n.

When the same plurality of substituents is assigned to various groups,the specific individual substituent assignment to each of such groups ismeant to be independently made with respect to the specific individualsubstituent assignments to the remaining groups. By way of illustration,but not as a limitation, if each of groups Q and R can be H or F, thechoice of H or F for Q is made independently of the choice of H or F forR, so the choice of assignment for Q does not determine or condition thechoice of assignment for R, or vice-versa, unless it is expresslyindicated otherwise. Illustrative claim recitation in this regard wouldread as “each of Q and R is independently H or F”, or “each of Q and Ris independently selected from the group consisting of H and F”.

Unless indicated otherwise, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof. Themethods for the determination of stereochemistry and the separation ofstereoisomers are well-known in the art.

In another example, a zwitterionic compound would be encompassed hereinby referring to a compound that is known to form a zwitterion, even ifit is not explicitly named in its zwitterionic form. Terms such aszwitterion, zwitterions, and their synonyms zwitterionic compound(s) arestandard IUPAC-endorsed names that are well known and part of standardsets of defined scientific names. In this regard, the name zwitterion isassigned the name identification CHEBI:27369 by the Chemical Entities ofBiological Interest (ChEBI) dictionary of molecular entities. Asgenerally well known, a zwitterion or zwitterionic compound is a neutralcompound that has formal unit charges of opposite sign. Sometimes thesecompounds are referred to by the term “inner salts”. Other sources referto these compounds as “dipolar ions”, although the latter term isregarded by still other sources as a misnomer. As a specific example,aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH,and it exists in some media (in this case in neutral media) in the formof the zwitterion ⁺H₃NCH₂COO⁻. Zwitterions, zwitterionic compounds,inner salts and dipolar ions in the known and well-established meaningsof these terms are within the scope of this invention, as would in anycase be so appreciated by those of ordinary skill in the art. Becausethere is no need to name each and every embodiment that would berecognized by those of ordinary skill in the art, no structures of thezwitterionic compounds that are associated with the compounds of thisinvention are given explicitly herein. They are, however, part of theembodiments of this invention. No further examples in this regard areprovided herein because the interactions and transformations in a givenmedium that lead to the various forms of a given compound are known byany one of ordinary skill in the art.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of the species for the same variableelsewhere in the formula, unless stated otherwise.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(exampie) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂, and S₃, this listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂, and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein.

The nomenclature “C_(i)-C_(j)” with j>i, when applied herein to a classof substituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁-C₃ or C₁₋₃ refers independently to embodiments that have onecarbon member (C₁, embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

A “pharmaceutically acceptable salt” is intended to mean a salt of anacid or base of a compound represented by Formula (I) that is non-toxic,biologically tolerable, or otherwise biologically suitable foradministration to the subject. See, generally, S. M. Berge, et al.,“Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook ofPharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth,Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceuticallyacceptable salts are those that are pharmacologically effective andsuitable for contact with the tissues of patients without unduetoxicity, irritation, or allergic response.

A compound of Formula (I) may possess a sufficiently acidic group, asufficiently basic group, or both types of functional groups, andaccordingly react with a number of inorganic or organic bases, andinorganic and organic acids, to form a pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

Compounds of Formula (I) may contain at least one nitrogen of basiccharacter, so desired pharmaceutically acceptable salts may be preparedby any suitable method available in the art, for example, treatment ofthe free base with an inorganic acid, such as hydrochloric acid,hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid,phosphoric acid, and the like, or with an organic acid, such as aceticacid, phenylacetic acid, propionic acid, stearic acid, lactic acid,ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid,succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid,oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid,lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonicacid, an alpha-hydroxy acid, such as mandelic acid, citric acid, ortartaric acid, an amino acid, such as aspartic acid or glutamic acid, anaromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoicacid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, anycompatible mixture of acids such as those given as examples herein, andany other acid and mixture thereof that are regarded as equivalents.

Compounds of Formula (I) may contain a carboxylic acid moiety, a desiredpharmaceutically acceptable salt may be prepared by any suitable method,for example, treatment of the free acid with an inorganic or organicbase, such as an amine (primary, secondary or tertiary), an alkali metalhydroxide, alkaline earth metal hydroxide, any compatible mixture ofbases such as those given as examples herein, and any other base andmixture thereof that are regarded as equivalents or acceptablesubstitutes in light of the ordinary level of skill in this technology.Illustrative examples of suitable salts include organic salts derivedfrom amino acids, such as glycine and arginine, ammonia, carbonates,bicarbonates, primary, secondary, and tertiary amines, and cyclicamines, such as benzylamines, pyrrolidines, piperidine, morpholine,piperazine, N-methyl-glucamine and tromethamine and inorganic saltsderived from sodium, calcium, potassium, magnesium, manganese, iron,copper, zinc, aluminum, and lithium.

The compounds of the invention, including their pharmaceuticallyacceptable salts, whether alone or in combination, (collectively,“active agent” or “active agents”) of the present invention are usefulas MGL-modulators in the methods of the invention. Such methods formodulating MGL comprise the use of a therapeutically effective amount ofat least one chemical entity of the invention.

In some embodiments, the MGL modulator is an inhibitor and is used in asubject diagnosed with or suffering from a disease, disorder, orcondition associated with MGL receptor activity, such as those describedherein. Symptoms or disease states are intended to be included withinthe scope of “disease, disorders or conditions.”

Accordingly, the invention relates to methods of using the active agentsdescribed herein to treat subjects diagnosed with or suffering from adisease, disorder, or condition associated with the MGL receptoractivity. The term “treat” or “treating” as used herein is intended torefer to administration of an active agent or composition of theinvention to a subject for the purpose of effecting a therapeutic orprophylactic benefit through modulation of MGL receptor activity.

Treating includes reversing, ameliorating, alleviating, inhibiting theprogress of, lessening the severity of, or preventing a disease,disorder, or condition, or one or more symptoms of such disease,disorder or condition associated with the MGL modulation. The term“subject” refers to a mammalian patient in need of such treatment, suchas a human.

The term “composition” refers to a product that includes the specifiedingredients in therapeutically effective amounts, as well as any productthat results, directly, or indirectly, from combinations of thespecified ingredients in the specified amounts.

The term “MGL inhibitor” is intended to encompass a compound thatinteracts with MGL to substantially reduce or eliminate its catalyticactivity, thereby increasing the concentrations of its substrate(s). Theterm “MGL-modulated” is used to refer to the condition of being affectedby the modulation of the MGL enzyme including the condition of beingaffected by the inhibition of the MGL enzyme. The disclosure is directedto methods for treating, ameliorating and/or preventing diseases,conditions, or disorders associated with pain (including inflammatorypain), and also psychiatric disorders, neurological disorders, cancersand eye conditions by the administration of therapeutically effectiveamounts of MGL modulators to subjects in need thereof.

The term “modulators” include both inhibitors and activators, where“inhibitors” refer to compounds that decrease, prevent, inactivate,desensitize, or down-regulate the MGL expression or activity, and“activators” are compounds that increase, activate, facilitate,sensitize, or up-regulate MGL expression or activity.

As used herein, unless otherwise noted, the term “affect” or “affected”(when referring to a disease, condition or disorder that is affected byinhibition of MGL) includes a reduction in the frequency and/or severityof one or more symptoms or manifestations of said disease, condition ordisorder; and/or include the prevention of the development of one ormore symptoms or manifestations of said disease, condition or disorderor the development of the disease, condition or disorder.

In treatment methods according to the invention, a therapeuticallyeffective amount of at least one active agent according to the inventionis administered to a subject suffering from or diagnosed as having sucha disease, disorder, or condition. A “therapeutically effective amount”means an amount or dose sufficient to generally bring about the desiredtherapeutic or prophylactic benefit in subjects in need of suchtreatment for the designated disease, disorder, or condition. Effectiveamounts or doses of the active agents of the present invention may beascertained by routine methods such as modeling, dose escalation studiesor clinical trials, and by taking into consideration routine factors,e.g., the mode or route of administration or drug delivery, thepharmacokinetics of the agent, the severity and course of the disease,disorder, or condition, the subject's previous or ongoing therapy, thesubject's health status and response to drugs, and the judgment of thetreating physician. For a 70-kg human, an illustrative range for asuitable dosage amount is from about 1 to 1000 mg/day in single ormultiple dosage units (e.g., BID, TID, QID or as required by modality).

Once improvement of the subject's disease, disorder, or condition hasoccurred, the dose may be adjusted for preventive or maintenancetreatment. For example, the dosage or the frequency of administration,or both, may be reduced as a function of the symptoms, to a level atwhich the desired therapeutic or prophylactic effect is maintained. Ofcourse, if symptoms have been alleviated to an appropriate level,treatment may cease. Subjects may, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

In addition, the compounds of the invention are envisaged for use alone,in combination with one or more of other compounds of this invention, orin combination with additional active ingredients in the treatment ofthe conditions discussed below. The additional active ingredients may beco-administered separately with at least one compound of the invention,with active agents of the invention or included with such an agent in apharmaceutical composition according to the invention. In anillustrative embodiment, additional active ingredients are those thatare known or discovered to be effective in the treatment of conditions,disorders, or diseases associated with the MGL modulation, such asanother MGL inhibitor or a compound active against another targetassociated with the particular condition, disorder, or disease. Thecombination may serve to increase efficacy (e.g., by including in thecombination a compound potentiating the potency or effectiveness of anagent according to the invention), decrease one or more side effects, ordecrease the required dose of the active agent according to theinvention.

When referring to inhibiting the target, an “effective amount” means anamount sufficient to affect MGL modulation.

The active agents of the invention are envisaged for use, alone or incombination with one or more additional active ingredients, to formulatepharmaceutical compositions of the invention. A pharmaceuticalcomposition of the invention comprises a therapeutically effectiveamount of at least one active agent in accordance with the invention.

Pharmaceutically acceptable excipients commonly used in pharmaceuticalcompositions are substances that are non-toxic, biologically tolerable,and otherwise biologically suitable for administration to a subject,such as an inert substance, added to a pharmacological composition orotherwise used as a vehicle, carrier, or diluent to facilitateadministration of an agent and that is compatible therewith. Examples ofsuch excipients include calcium carbonate, calcium phosphate, varioussugars and types of starch, cellulose derivatives, gelatin, vegetableoils, and polyethylene glycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the active agents may be prepared using pharmaceuticallyacceptable excipients and compounding techniques known or that becomeavailable to those of ordinary skill in the art. The compositions may beadministered in the inventive methods by a suitable route of delivery,e.g., oral, parenteral, rectal, topical, or ocular routes, or byinhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. The compositions may be formulated forany one of a plurality of administration routes, such as intravenousinfusion, topical administration, or oral administration. Preferably,the compositions may be formulated for oral administration.

For oral administration, the active agents of the invention can beprovided in the form of tablets or capsules, or as a solution, emulsion,or suspension. To prepare the oral compositions, the active agents maybe formulated to yield a dosage of, e.g., for a 70-kg human, anillustrative range for a suitable dosage amount is from about 1 to 1000mg/day in single or multiple dosage units.

Oral tablets may include the active ingredient(s) mixed with compatiblepharmaceutically acceptable excipients such as diluents, disintegratingagents, binding agents, lubricating agents, sweetening agents, flavoringagents, coloring agents and preservative agents. Suitable inert fillersinclude sodium and calcium carbonate, sodium and calcium phosphate,lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate,mannitol, sorbitol, and the like. Exemplary liquid oral excipientsinclude ethanol, glycerol, water, and the like. Starch,polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystallinecellulose, and alginic acid are exemplary disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, may be magnesium stearate, stearic acid or talc. If desired,the tablets may be coated with a material such as glyceryl monostearateor glyceryl distearate to delay absorption in the gastrointestinal tractor may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin or(hydroxypropyl)methyl cellulose capsules. To prepare hard gelatincapsules, active ingredient(s) may be mixed with a solid, semi-solid, orliquid diluent. Liquids for oral administration may be in the form ofsuspensions, solutions, emulsions or syrups or may be lyophilized orpresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid compositions may optionallycontain: pharmaceutically-acceptable excipients such as suspendingagents (for example, sorbitol, methyl cellulose, sodium alginate,gelatin, hydroxyethyl cellulose, carboxymethylcellulose, aluminumstearate gel and the like); non-aqueous vehicles, e.g., oil (forexample, almond oil or fractionated coconut oil), propylene glycol,ethyl alcohol, or water; preservatives (for example, methyl or propylp-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and,if desired, flavoring or coloring agents.

The active agents of this invention may also be administered by non-oralroutes. For example, compositions may be formulated for rectaladministration as a suppository, enema or foam. For parenteral use,including intravenous, intramuscular, intraperitoneal, or subcutaneousroutes, the agents of the invention may be provided in sterile aqueoussolutions or suspensions, buffered to an appropriate pH and isotonicityor in parenterally acceptable oil. Suitable aqueous vehicles includeRinger's solution and isotonic sodium chloride. Such forms may bepresented in unit-dose form such as ampules or disposable injectiondevices, in multi-dose forms such as vials from which the appropriatedose may be withdrawn, or in a solid form or pre-concentrate that can beused to prepare an injectable formulation. Illustrative infusion dosesrange from about 1 to 1000 μg/kg/minute of agent admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days.

For topical administration, the agents may be mixed with apharmaceutical carrier at a concentration of about 0.01% to about 20% ofdrug to vehicle, preferably 0.1% to 10%. Another mode of administeringthe agents of the invention may utilize a patch formulation to affecttransdermal delivery.

Active agents may alternatively be administered in methods of thisinvention by inhalation, via the nasal or oral routes, e.g., in a sprayformulation also containing a suitable carrier.

In a further embodiment, the invention is directed to a method oftreating a subject suffering from or diagnosed with a disease, disorder,or condition associated with MGL modulation, comprising administering tothe subject in need of such treatment a therapeutically effective amountof the active agent.

The compounds of Formula (I) are useful in methods for treating,ameliorating and/or preventing a disease, a condition or a disorder thatis affected by the inhibition of MGL. Such methods compriseadministering to a subject, including an animal, a mammal, and a humanin need of such treatment, amelioration and/or prevention, atherapeutically effective amount of a compound of Formula (I), or anenantiomer, diastereomer, solvate or pharmaceutically acceptable saltthereof.

In particular, the compounds of Formula (I), or pharmaceuticallyacceptable salts, isotopes, N-oxides, solvates and stereoisomersthereof, are useful for treating, ameliorating and/or preventingdiseases, conditions, or disorders causing pain, psychiatric disorders,neurological disorders, cancers and eyes conditions. More particularly,the compounds of Formula (I), or pharmaceutically acceptable salts,isotopes, N-oxides, solvates and stereoisomers thereof, are useful fortreating, ameliorating and/or preventing inflammatory pain, majordepressive disorder, treatment resistant depression, anxious depressionor bipolar disorder by administering to a subject in need thereof atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, isotope, N-oxide, solvate orstereoisomer thereof as herein defined.

1) Pain Examples of inflammatory pain include, but are not limited to,pain due to a disease, condition, disorder, or a pain state includinginflammatory bowel disease, visceral pain, migraine, post-operativepain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain,joint pain, abdominal pain, chest pain, labor, musculoskeletal diseases,skin diseases, toothache, pyresis, burn, sunburn, snake bite, venomoussnake bite, spider bite, insect sting, neurogenic bladder, interstitialcystitis, urinary tract infection, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis,enteritis, irritable bowel syndrome, cholecystitis, pancreatitis,postmastectomy pain syndrome, menstrual pain, endometriosis, pain due tophysical trauma, headache, sinus headache, tension headache, orarachnoiditis.

One type of inflammatory pain is inflammatoryhyperalgesia/hypersensitivity. Examples of inflammatory hyperalgesiainclude a disease, condition, disorder, or pain state includinginflammation, osteoarthritis, rheumatoid arthritis, back pain, jointpain, abdominal pain, musculoskeletal diseases, skin diseases,post-operative pain, headaches, toothache, burn, sunburn, insect sting,neurogenic bladder, urinary incontinence, interstitial cystitis, urinarytract infection, cough, asthma, chronic obstructive pulmonary disease,rhinitis, contact dermatitis/hypersensitivity and/or dermal allergy,itch, eczema, pharyngitis, enteritis, irritable bowel syndrome,inflammatory bowel diseases including Crohn's Disease, ulcerativecolitis, benign prostatic hypertrophy, and nasal hypersensitivity.

In an embodiment, the present invention is directed to a method fortreating, ameliorating and/or preventing inflammatory visceralhyperalgesia in which an enhanced visceral irritability exists,comprising, consisting of, and/or consisting essentially of the step ofadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt, isotope, N-oxide, solvate or stereoisomer thereof. In afurther embodiment, the present invention is directed to a method fortreating inflammatory somatic hyperalgesia in which a hypersensitivityto thermal, mechanical and/or chemical stimuli exists, comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

A further embodiment of the present invention is directed to a methodfor treating, ameliorating and/or preventing neuropathic pain. Examplesof a neuropathic pain include pain due to a disease, condition,disorder, or pain state including cancer, neurological disorders, spineand peripheral nerve surgery, brain tumor, traumatic brain injury (TBI),spinal cord trauma, chronic pain syndrome, fibromyalgia, chronic fatiguesyndrome, lupus, sarcoidosis, peripheral neuropathy, bilateralperipheral neuropathy, diabetic neuropathy, central pain, neuropathiesassociated with spinal cord injury, stroke, amyotrophic lateralsclerosis (ALS), Parkinson's disease, multiple sclerosis, sciaticneuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis,stump pain, phantom limb pain, bony fractures, oral neuropathic pain,Charcot's pain, complex regional pain syndrome I and II (CRPS I/II),radiculopathy, Guillain-Barre syndrome, meralgia paresthetica,burning-mouth syndrome, optic neuritis, postfebrile neuritis, migratingneuritis, segmental neuritis, Gombault's neuritis, neuronitis,cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia,glossopharyngeal neuralgia, migrainous neuralgia, idiopathic neuralgia,intercostals neuralgia, mammary neuralgia, Morton's neuralgia,nasociliary neuralgia, occipital neuralgia, postherpetic neuralgia,causalgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia,supraorbital neuralgia, trigeminal neuralgia, vulvodynia, vidianneuralgia or chemotherapy-induced neuropathy.

One type of neuropathic pain is neuropathic cold allodynia, which can becharacterized by the presence of a neuropathy-associated allodynic statein which a hypersensitivity to cooling stimuli exists. Examples ofneuropathic cold allodynia include allodynia due to a disease,condition, disorder or pain state including neuropathic pain(neuralgia), pain arising from spine and peripheral nerve surgery ortrauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpeticneuralgia, causalgia, peripheral neuropathy, diabetic neuropathy,central pain, stroke, peripheral neuritis, polyneuritis, complexregional pain syndrome I and II (CRPS I/II) and radiculopathy.

In a further embodiment, the present invention is directed to a methodfor treating, ameliorating and/or preventing neuropathic cold allodyniain which a hypersensitivity to a cooling stimulus exists, comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt, isotope, N-oxide, solvate or stereoisomer thereof

-   -   2) Psychiatric Disorders

Examples of psychiatric disorders include, but are not limited to,anxieties such as, social anxiety, post-traumatic stress disorder,phobias, social phobia, special phobias, panic disorder,obsessive-compulsive disorder, acute stress disorder, separation anxietydisorder, and generalized anxiety disorder, as well as depression suchas, major depression, bipolar disorder, seasonal affective disorder,post-natal depression, manic depression, and bipolar depression, mooddisorders and mood affective disorders that can be treated according tothe present invention include, but are not limited to, bipolar disorderI depressed, hypomanic, manic and mixed form; bipolar disorder II;depressive disorders, such as single depressive episode or recurrentmajor depressive disorder, minor depressive disorder,treatment-resistant depression, anxious depression, bipolar disorder,depressive disorder with postpartum onset, depressive disorders withpsychotic symptoms; persistent mood disorders, such as cyclothymia,dysthymia, euthymia; and premenstrual dysphoric disorder; psychoses.

3) Neurological Disorders

Examples of neurological disorder include, but are not limited to,tremors, dyskinesias, dystonias, spasticity, Tourette's Syndrome;neuromyelitis optica, Parkinson's disease; Alzheimer's disease; seniledementia; Huntington's disease; Epilepsy/seizure disorders and sleepdisorders.

4) Cancers:

Examples of cancers include, but are not limited to, benign skin tumors,prostate tumors, ovarian tumors and cerebral tumors (glioblastomas,medulloepitheliomas, medulloblastomas, neuroblastomas, tumors ofembryonic origin, astrocytomas, astroblastomas, ependymomas,oligodendrogliomas, neuroepitheliomas, epiphyseal tumor,ependymoblastomas, malignant meningiomas, sarcomatosis, malignantmelanomas, schwannomas).

5) Eye Conditions

Examples of eye conditions include, but are not limited to, ocularhypertension, glaucoma, degeneration, and apoptosis of retinal ganglioncells and neuroretinal cells.

Other embodiments of this invention provide for a method for modulatingMGL receptor activity, including when such receptor is in a subject,comprising exposing MGL receptor to a therapeutically effective amountof at least one compound selected from compounds of the invention.

Embodiments of this invention are compounds of Formula (I),

wherein

X is CH₂ or O;

Y is selected from the group consisting of:

R¹ is H;

R^(2a) and R^(2b) are each independently H;

R³ is selected from the group consisting of: 2,3-dihydro-1H-indene;pyridyl substituted with C₁₋₆alkyl; phenyl; and phenyl substituted withone or two members each independently selected from the group consistingof: halo, C₁₋₆alkyl, C₁₋₆alkyl substituted with OH, C₁₋₆alkylsubstituted with CO₂H, C₁₋₆haloalkyl, OC₁₋₆haloalkyl, C₃₋₆cycloalkyl,O-phenyl, and C₃₋₆cycloalkyl substituted with CH₃;

R^(a) and R^(b) are each independently selected from the groupconsisting of: H and halo; and R^(c) is H or CH₃;

and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers thereof.

An additional embodiment of the invention is a compound of Formula (I)wherein X is CH₂.

An additional embodiment of the invention is a compound of Formula (I)wherein X is O.

An additional embodiment of the invention is a compound of Formula (I)wherein Y is

An additional embodiment of the invention is a compound of Formula (I)wherein Y is

An additional embodiment of the invention is a compound of Formula (I)wherein Y is

An additional embodiment of the invention is a compound of Formula (I)wherein R^(a) and R^(b) are H.

An additional embodiment of the invention is a compound of Formula (I)wherein R^(a) and R^(b) are each independently H and Cl.

An additional embodiment of the invention is a compound of Formula (I)wherein R^(a) and R^(b) are F.

An additional embodiment of the invention is a compound of Formula (I)wherein R³ is

An additional embodiment of the invention is a compound of Formula (I)wherein R³ phenyl, or phenyl substituted with one or two members eachindependently selected from the group consisting of: Cl, F, CH₃, CH₂CH₃,CH(CH₃)₂, C(CH₃)₃, CH₂CH(CH₃)₂, C(CH₃)₂CH₂OH, C(CH₃)₂CH₂CO₂H, CF₃, OCF₃,cyclopropyl, cyclopropyl substituted with CH₃, and O-phenyl.

An additional embodiment of the invention is a compound of Formula (I)wherein R³ is

An additional embodiment of the invention is a compound of Formula (I)wherein R³ is 3-tert-butylphenyl, 4-tert-butylphenyl,4-methyl-3-trifluoromethylphenyl, or 3,4-dimethylphenyl.

A further embodiment of the current invention is a compound as shownbelow in Table 1.

Ex # Compound Name 1(rac)-(2s,4s)-2-(1-(p-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 2(2s,4*R)-2-((1*S,5*R)-1-(p-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 3(2s,4*S)-2-((1*R,5*S)-1-(p-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 4(rac)-(2s,4s)-2-(1-Phenyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 5(rac)-(2s,4s)-2-(1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 6(rac)-(2s,4s)-2-(1-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 7 (2s,4*S)-2-((1*R,5*S)-1-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 8(2s,4*R)-2-((1*S,5*R)-1-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 9(rac)-(2s,4s)-2-(1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 10 (2s,4*S)-2-((1*R,5*S)-1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 11(2s,4*R)-2-((1*S,5*R)-1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 12(rac)-(2r,4s)-2-(1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 13(rac)-(2r,4s)-2-(1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 14(2r,4*S)-2-((1*R,5*S)-1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 15(2r,4*R)-2-((1*S,5*R)-1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 16(rac)-(2s,4s)-2-(1-(3-Cyclopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 17(rac)-(2s,4s)-2-(1-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 18(rac)-(2s,4s)-2-(1-(4-Cyclopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 19 (rac)-(2s,4s)-2-(1-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 20(rac)-(2s,4s)-2-(1-(o-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 21(rac)-(2s,4s)-2-(1-(m-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 22(rac)-(2s,4s)-2-(1-(4-(Trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 23(rac)-(2s,4s)-2-(1-(3-(Trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 24(rac)-(2s,4s)-2-(1-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 25(rac)-(2s,4s)-2-(1-(4-Methyl-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 26(rac)-(2s,4s)-2-(1-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 27(rac)-(2r,4s)-2-(1-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 28(rac)-(2s,4s)-2-(1-(4-Phenoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 29(rac)-(2s,4s)-2-(1-(3-Phenoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 30(rac)-(2s,4s)-2-(1-(3-Chloro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 31(rac)-(2s,4s)-2-(1-(3-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 32(rac)-(2s,4s)-2-(1-(4-Cyclopropy1-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 33(rac)-(2s,4s)-2-(1-(2-Methyl-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 34(rac)-(2s,4s)-2-(1-(2-Methyl-4-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 35(rac)-(2s,4s)-2-(1-(3-Methyl-4-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 36(rac)-(2s,4s)-2-(1-(3-Methyl-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 37(rac)-(2s,4s)-2-(1-(3-Fluoro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 38 (2s,4S)-2-((1R,5S,6S)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicy clo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 39(rac)-(2s,4s)-2-(6-Phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 40(2s,4S)-2-((1R,6S)-6-Phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 41(2s,4R)-2-((1S,6R)-6-Phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 42(rac)-(2s,4s)-2-(7,7-Difluoro-6-phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 43(rac)-(2s,4s)-2-(6-(m-Tolyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 44(2s,4*R)-2-((1*S,6*R)-6-(m-Tolyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 45(2s,4*S)-2-((1*R,6*S)-6-(m-Tolyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 46(rac)-(2s,4s)-2-(6-(3-Fluoro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 47(2s,4*R)-2-((1*S,6*R)-6-(3-Fluoro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 48(2s,4*S)-2-((1*R,6*S)-6-(3-Fluoro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 49(rac)-(2s,4s)-2-(6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 50(2s,4*R)-2-((1*S,6*R)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 51(2s,4*S)-2-((1*R,6*S)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 52(rac)-(2r,4s)-2-(6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 53(rac)-(2s,4s)-2-(6-(o-Tolyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 54(rac)-(2s,4s)-2-(6-(4-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 55(rac)-(2r,4s)-2-(6-(4-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 56(rac)-(2s,4s)-2-(6-(p-Tolyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 57(rac)-(2s,4s)-2-(6-(3-(Trifluoromethyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 58(rac)-(2s,4s)-2-(6-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 59(rac)-(2r,4s)-2-(6-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 60(rac)-(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 61(rac)-(2r,4s)-2-(6-(3-(tert-Butyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 62(rac)-(2s,4s)-2-(6-(4-(tert-Butyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 63(rac)-(2r,4s)-2-(6-(4-(tert-Butyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 64(rac)-(2s,4s)-2-(6-(3-Cyclopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 65(rac)-(2r,4s)-2-(6-(3-Cyclopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 66(rac)-(2s,4s)-2-(6-(4-Cyclopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 67(rac)-(2s,4s)-2-(6-(3-Chloro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 68(rac)-(2r,4s)-2-(6-(3-Chloro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 69(rac)-(2s,4s)-2-(6-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 70(rac)-(2r,4s)-2-(6-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 71(rac)-(2s,4s)-2-(6-(3-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 72(rac)-(2s,4s)-2-(6-(4-Cyclopropy1-2-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 73(rac)-(2s,4s)-2-(6-(3-Isopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 74(rac)-(2s,4s)-2-(6-(4-Isopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 75(rac)-(2s,4s)-2-(6-(4-Methyl-3-(trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 76(rac)-(2r,4s)-2-(6-(4-Methyl-3-(trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 77(rac)-(2s,4s)-2-(1-Phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 78(2s,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 79(2r,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 80(2s,4S)-2-((1R,5S,6S)-6-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 81(2r,4S)-2-((1R,5S,6S)-6-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 82(2s,4S)-2-((1R,5S,6S)-6-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 83(2r,4S)-2-((1R,5S,6S)-6-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 84(2s,4S)-2-((1R,5S,6S)-6-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 85(2s,4S)-2-((1R,5S,6S)-6-(4-Methyl-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 86(2s,4S)-2-((1R,5S,6S)-6-(4-Ethylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 87(2r,4S)-2-((1R,5S,6S)-6-(4-Ethylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 88(2s,4S)-2-((1R,5S,6S)-6-(3,4-Dimethylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 89(2r,4S)-2-((1R,5S,6S)-6-(3,4-Dimethylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 90(2s,4S)-2-((1R,5S,6S)-6-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 91(2r,4S)-2-((1R,5S,6S)-6-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 92(2s,4S)-2-((1R,5S,6S)-6-(2,3-Dihydro-lH-inden-5-yl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; and 93(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-6-(3-(tert-Butyl)phenyl)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 94(rac)-(25,45)-2-(1-(4-Ethylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 95(2r,4*S)-2-((1*R,5*S)-1-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 96(2r,4*R)-2-((1*5,5*R)-1-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 97(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-1-Methyl-6-(o-tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 98(2s,4S)-2-((1R,5S,6S)-6-(o-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 99(2s,4*S)-2-((1*R,5*S,6*R)-6-(3-(tert-Butyl)phenyl)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;100 (2s,4*R)-2-((1*S,5*R,6*S)-6-(3-(tert-Butyl)phenyl)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;101(2s,4S)-2-((1R,5S,6S)-6-(3-Isobutylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 102(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-6-(3,4-Dimethylphenyl)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;103(2s,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl-5-D)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 104(2s,4S)-2-((1R,55,6S)-6-(3-(1-Hydroxy-2-methylpropan-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;1052-Methyl-2-(3-((1R,5S,6S)-3-((2s,4S)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)phenyl)propanoic acid; 106(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-1-Methyl-6-(3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;107(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-1-Methyl-6-(4-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;108 (rac)-(2s,4*S)-2-((1*R,5*S,6*R)-6-(4-Cyclopropylphenyl)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;109(2s,4S)-2-((1R,5S,6S)-6-(4-Cyclopropy1-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 110(2s,4S)-2-((1R,5S,6S)-6-(3-Chloro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 111(2s,4S)-2-((1R,5S,6S)-6-(3-Ethy1-4-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 112(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-1-Methyl-6-(4-methyl-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;113 (2s,4S)-2-((1R,5S,6S)-6-(2-Methyl-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;114(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-1-Methyl-6-(4-methyl-3-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;115 (2s,4S)-2-((1R,5S,6S)-6-(4-Methyl-3-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;116(2s,4S)-2-((1R,5S,6R)-6-(6-(tert-Butyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 117(2s,4*R)-2-((1*S,6*R)-6-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 118(2s,4*S)-2-((1*R,6*S)-6-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 119(2r,4*S)-2-((1*R,6*S)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 120(2r,4*R)-2-((1*S,6*R)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 121(2r,4*S)-2-((1*R,6*S)-6-(4-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 122(2r,4*R)-2-((1*S,6*R)-6-(4-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 123(rac)-(2S,4S)-2-(7-Chloro-6-phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; and 124(rac)-(2s,4s)-2-(7,7-Dichloro-6-phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers thereof.

A further embodiment of the current invention is a compound selectedfrom the group consisting of:

(rac)-(2s,4s)-2-(1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;

(2s,4*R)-2-((1*S,6*R)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;

(2s,4*S)-2-((1*R,6*S)-6(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;

(2s,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;and

(2r,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers thereof.

A further embodiment of the current invention is a compound that is(rac)-(2s,4s)-2-(1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers thereof.

A further embodiment of the current invention is a compound that is(2s,4*R)-2-((1*S,5*R)-1-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one,and pharmaceutically acceptable salts thereof.

A further embodiment of the current invention is a compound that is(2s,4*R)-2-((1*S,6*R)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one,and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers thereof.

A further embodiment of the current invention is a compound that is(2s,4*S)-2-((1*R,6*S)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one,and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers thereof.

A further embodiment of the current invention is a compound that is(2s,4S)-2-((1R,5S,6S)-6-(3-Chloro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one,and pharmaceutically acceptable salts thereof

A further embodiment of the current invention is a compound that is(2s,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one,and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers thereof.

A further embodiment of the current invention is a compound that is(2s,4*S)-2-((1*R,6*5)-6-(3-Fluoro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one,and pharmaceutically acceptable salts thereof.

A further embodiment of the current invention is a compound that is(2r,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one,and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers thereof.

An additional embodiment of the invention is a compound of Formula (I)having the Formula (IA):

wherein

X is CH₂ or O; and

R³ is selected from the group consisting of: phenyl; phenyl substitutedwith one or two members each independently selected from the groupconsisting of: halo, C₁₋₆alkyl, C₁₋₆haloalkyl, OC₁₋₆haloalkyl,C₃₋₆cycloalkyl, O-phenyl, and C₃₋₆cycloalkyl substituted with CH₃. Anadditional embodiment of the invention is a compound of Formula (I)having the Formula (IB):

wherein

X is CH₂ or O;

R³ is selected from the group consisting of: 2,3-dihydro-1H-indene;pyridyl substituted with C₁₋₆alkyl; phenyl substituted with one or twomembers each independently selected from the group consisting of: halo,C₁₋₆alkyl, C₁₋₆alkyl substituted with OH, C₁₋₆alkyl substituted withCO₂H, C₁₋₆haloalkyl, OC₁₋₆haloalkyl and cyclopropyl; and

R^(c) is H or CH₃.

An additional embodiment of the invention is a compound of Formula (I)having the Formula (IC):

wherein

X is CH₂ or O;

R³ is selected from the group consisting of: phenyl; phenyl substitutedwith one or two members each independently selected from the groupconsisting of: halo, C₁₋₆alkyl, C₁₋₆haloalkyl, OC₁₋₆haloalkyl,C₃₋₆cycloalkyl, and C₃₋₆cycloalkyl substituted with CH₃; and

R^(a) and R^(b) are each independently selected from the groupconsisting of: H, Cl and F.

-   -   An additional embodiment of the invention is a pharmaceutical        composition comprising: (A) a therapeutically effective amount        of at least one compound selected from compounds of Formula (I)

wherein

X is CH₂ or O;

Y is selected from the group consisting of:

R¹ is H;

R^(2a) and R^(2b) are each independently H;

R³ is selected from the group consisting of: 2,3-dihydro-1H-indene;pyridyl substituted with C₁₋₆alkyl; phenyl; and phenyl substituted withone or two members each independently selected from the group consistingof: halo, C₁₋₆alkyl, C₁₋₆alkyl substituted with OH, C₁₋₆alkylsubstituted with CO₂H, C₁₋₆haloalkyl, OC₁₋₆haloalkyl, C₃₋₆cycloalkyl,O-phenyl, and C₃₋₆cycloalkyl substituted with CH₃;

R^(a) and R^(b) are each independently selected from the groupconsisting of: H and halo; and

R^(c) is H or CH₃;

and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers of compounds of Formula (I);

and (B) at least one pharmaceutically acceptable excipient.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound in Table 1, as well as and pharmaceutically acceptablesalts, isotopes, N-oxides, solvates, and stereoisomers of compounds ofTable 1, pharmaceutically acceptable prodrugs of compounds of Table 1,and pharmaceutically active metabolites of Table 1; and at least onepharmaceutically acceptable excipient.

An additional embodiment of the invention is a method of treating asubject suffering from or diagnosed with a disease, disorder, orcondition mediated by MGL receptor activity, comprising administering toa subject in need of such treatment a therapeutically effective amountof at least one compound selected from compounds of Formula (I):

wherein

X is CH₂ or O;

Y is selected from the group consisting of:

R¹ is H;

R^(2a) and R^(2b) are each independently H;

R³ is selected from the group consisting of: 2,3-dihydro-1H-indene;pyridyl substituted with C₁₋₆alkyl; phenyl; and phenyl substituted withone or two members each independently selected from the group consistingof: halo, C₁₋₆alkyl, C₁₋₆alkyl substituted with OH, C₁₋₆alkylsubstituted with CO₂H, C₁₋₆haloalkyl, OC₁₋₆haloalkyl, C₃₋₆cycloalkyl,O-phenyl, and C₃₋₆cycloalkyl substituted with CH₃;

R^(a) and R^(b) are each independently selected from the groupconsisting of: H and halo; and

R^(c) is H or CH₃;

and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers thereof, to a subject in need thereof.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound of Formula (IA), as well as pharmaceutically acceptablesalts, N-oxides or solvates of compounds of Formula (IA),pharmaceutically acceptable prodrugs of compounds of Formula (IA), andpharmaceutically active metabolites of Formula (IA); and at least onepharmaceutically acceptable excipient.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound of Formula (IB), as well as pharmaceutically acceptablesalts, N-oxides or solvates of compounds of Formula (IB),pharmaceutically acceptable prodrugs of compounds of Formula (IB), andpharmaceutically active metabolites of Formula (IB); and at least onepharmaceutically acceptable excipient.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound of Formula (IC), as well as pharmaceutically acceptablesalts, N-oxides or solvates of compounds of Formula (IC),pharmaceutically acceptable prodrugs of compounds of Formula (IC), andpharmaceutically active metabolites of Formula (IC); and at least onepharmaceutically acceptable excipient.

Also within the scope of the invention are enantiomers and diastereomersof the compounds of Formula (I) (as well as Formulas (IA), (IB), and(IC)) Also within the scope of the invention are the pharmaceuticallyacceptable salts, N-oxides or solvates of the compounds of Formula (I)(as well as Formulas (IA), (IB), and (IC)). Also within the scope of theinvention are the pharmaceutically acceptable prodrugs of compounds ofFormula (I) (as well as Formulas (IA), (IB), and (IC)), andpharmaceutically active metabolites of the compounds of Formula (I) (aswell as Formulas (IA), (IB), and (IC)).

Also within the scope of the invention are isotopic variations ofcompounds of Formula (I) (as well as Formulas (IA), (IB), and (IC)),such as, e.g., deuterated compounds of Formula (I). Also within thescope of the invention are the pharmaceutically acceptable salts,N-oxides or solvates of the isotopic variations of the compounds ofFormula (I) (as well as Formulas (IA), (IB), and (IC)). Also within thescope of the invention are the pharmaceutically acceptable prodrugs ofthe isotopic variations of the compounds of Formula (I) (as well asFormulas (IA), (IB), and (IC)), and pharmaceutically active metabolitesof the isotopic variations of the compounds of Formula (I) (as well asFormulas (IA), (IB), and (IC)).

An additional embodiment of the invention is a method of treating asubject suffering from or diagnosed with a disease, disorder, orcondition mediated by MGL receptor activity, comprising administering toa subject in need of such treatment a therapeutically effective amountof at least one compound selected from compounds of Formula (I) (as wellas Formulas (IA), (IB), and (IC)), enantiomers and diastereomers of thecompounds of Formula (I) (as well as Formulas (IA), (IB), and (IC)),isotopic variations of the compounds of Formula (I) (as well as Formulas(IA), (IB), and (IC)), and pharmaceutically acceptable salts of all ofthe foregoing.

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables are asdefined above in reference to Formula (I). Reactions may be performedbetween the melting point and the reflux temperature of the solvent, andpreferably between 0° C. and the reflux temperature of the solvent.Reactions may be heated employing conventional heating or microwaveheating. Reactions may also be conducted in sealed pressure vesselsabove the normal reflux temperature of the solvent.

Abbreviations and acronyms used herein include the following:

TABLE 2 Term Acronym Bis(triphenylphosphine)palladium(II) dichloridePdCl₂(PPh₃)₂ Microliter μL or uL Acetonitrile ACN, MeCN Aqueous aqAtmosphere atm tert-Butyloxycarbonyl BOC or Boc Benzotriazo1-1-yloxy-BOP tris(dimethylamino)phosphonium hexafluorophosphate Broad brMesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2′- CatacXium ®amino-1,1′-biphenyl)]palladium(II) A Pd G3 Diatomaceous Earth Celite ®1,8-Diazabicyclo[5.4.0]undec-7-ene DBU N,N′-Dicyclohexylcarbodiimide DCCDichloromethane DCM Diisobutylaluminum hydride DIBAL-H Diisopropyl etherDIPE N-Ethyldiisopropylamine DIPEA 4-Dimethylaminopyridine DMAP1,2-Dimethoxyethane DME Dimethylformamide DMF Dimethylsulfoxide DMSO1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EDC, EDAC or EDCIElectrospray ionization ESI Diethyl ether Ether, Et₂O Ethyl AcetateEtOAc, or EA Ethanol EtOH Norma1-phase silica gel chromatography FCCGrams g Hours h, hr, hrs 1-[Bis(dimethylamino)methylene]-1H-1,2,3- HATUtriazolo[4,5-b]pyridinium 3-oxide hexafluorophosphateN,N,N′,N′Tetramethyl-O-(1H-benzotriazol-1- HBTU yl)uroniumhexafluorophosphate Hydroxybenzotriazole HOBt High-pressure liquidchromatography HPLC Hertz Hz Isopropyl alcohol iPrOH, IPA Potassiumtert-butoxide KOtBu Lithium aluminum hydride LAH Liquid chromatographyand mass spectrometry LCMS Molar M Mass to charge ratio m/z MethanolMeOH Milligrams mg Minute min Milliliter mL Millimoles mmol Massspectrometry MS Normal N Sodium acetate NaOAc N-Bromosuccinimide NBSNuclear magnetic resonance NMR Palladium on carbon Pd/CBis(dibenzylideneacetone)palladium Pd(dba)₂ Bis(diphenylphosphino)Pd(dppf)Cl₂ ferrocene]dichloropalladium(II)Tetrakis(triphenylphosphine)palladium Pd(PPh₃)₄ Parts per million ppmProtecting Group PG Precipitate ppt Polytetrafluoroethylene PTFEBromotripyrrolidinophosphonium hexafluorophosphate PyBroP ® ReversePhase RP Retention time R_(t) Room temperature rt Saturated satSupercritical Fluid Chromatography SFC2-Dicyclohexylphosphino-2′,6″-dimethoxybiphenyl SPhos Temperature T2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane- T3P ® 2,4,6-trioxideTriethylamine TEA Trifluoroacetic acid TFA Trifluoroacetic anhydrideTFAA Tetrahydrofuran THF Thin layer chromatography TLCN,N,N′,N′-Tetramethylethylenediamine TMEDA Volume in milliliters ofsolvent per gram of substrate V, or volumes

PREPARATIVE EXAMPLES

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples to follow.

According to SCHEME 1, a compound of formula (V), where R^(a) isC₁₋₄alkyl, is treated with hydroxylamine; using an additive such assodium acetate (NaOAc), and the like; in a suitable solvent such asethanol (EtOH), and the like; to provide a compound of formula (VI). Acompound of formula (VII) is prepared from a compound of formula (VI)using an oxidant such as hydrogen peroxide, urea-hydrogen peroxide, andthe like; in the presence of an activator such as trifluoroaceticanhydride (TFAA), and the like; in the presence of a base such asdibasic sodium phosphate, and the like; in a solvent such asacetonitrile (ACN), and the like.

According to SCHEME 2, compounds of formula (VIIIa) and (VIIIb) areprepared by reacting a compound of formula (VII), where R^(a) isC₁₋₄alkyl, with formaldehyde in the presence of a base such astriethylamine (TEA), and the like; in a solvent such as ACN, and thelike. A compound of formula (IX) is prepared by hydrogenolysis of acompound of formula (VIIIb) under an atmosphere of hydrogen gas (H₂) inthe presence of a catalyst such as palladium on carbon (Pd/C), and thelike; in a solvent such as ethyl acetate (EtOAc), EtOH, and the like. Acompound of formula (X) is prepared by the reaction of a compound offormula (IX) with triphosgene in the presence of a base such as TEA, andthe like; in a solvent such as tetrahydrofuran (THF), and the like. Acompound of formula (XI) is prepared by the acidic deprotection of acompound of formula (X) using an acid such as trifluoroacetic acid(TFA), HCl in dioxane, and the like.

According to SCHEME 3, compounds of formula (XIIa) and formula (XIIb)are prepared by a Michael-type reaction between a compound of formula(VII), where R^(a) is ethyl; and methyl acrylate; in the presence of abase such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the like; ina solvent such as ACN, and the like. Reductive ring closure of acompound of formula (XIIa) using a reducing agent such as sodiumborohydride (NaBH₄), and the like; an additive such as nickel(II)chloride hexahydrate, and the like; in a suitable solvent such asmethanol (MeOH), and the like; provides a compound of formula (XIII),where X is CH₂.

According to SCHEME 4, a compound of formula (XIV) may be prepared byreacting a compound of formula (VII), where R^(a) is C₁₋₄alkyl; withacetaldehyde in the presence of a base such as TEA, and the like; in asolvent such as ACN, and the like, at temperatures ranging from 0° C. toroom temperature, for a period of 18 h. A compound of formula (XIV) maybe subjected to hydrogenolysis; employing conditions previouslydescribed, to provide compounds of formula (XVa) and (XVb).

According to SCHEME 5, a compound of formula (XVa), where R^(a) isC₁₋₄alkyl, may be subjected to ring closure conditions with triphosgene,employing conditions previously described, to provide a compound offormula (XVI). A compound of formula (XVI) may be subjected to acidicdeprotection conditions previously described to provide a compound offormula (XVII), where X is O.

According to SCHEME 6, a commercially available or syntheticallyaccessible compound of formula (XVIII), is reacted in a Simmons-Smithtype reaction to provide a compound of formula (XIX). For example,compound of formula (XVIII), where PG is BOC, and n is independently 1or 2, is reacted with diethylzinc; diiodomethane; and TFA; in a suitablesolvent such as dichloromethane (DCM), and the like; at temperaturesranging from −40° C. to −15° C. The BOC protecting group is cleavedunder these conditions. Boc protection is achieved employingdi-tert-butyl dicarbonate; a suitable base such as TEA, and the like;and 4-dimethylaminopyridine (DMAP); in a suitable solvent such as THF,DCM, and the like; to provide a compound of formula (XIX). A compound offormula (XIX) is treated with potassium bifluoride (KHF₂) in a suitablesolvent such as MeOH, and the like; at temperatures ranging from rt tothe reflux temperature of the solvent; to provide a compound of formula(XX).

According to SCHEME 7, a compound of formula (XX), where n isindependently 1 or 2, and PG is BOC, is reacted with a variablysubstituted bromobenzene of formula (XXI), where R³ is a suitablysubstituted aryl group; a catalyst such asmesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II)(CatacXium® A Pd G3), and the like; a base such as cesium carbonate(Cs₂CO₃), and the like; in a mixture of solvents such as toluene/water,and the like; at a temperature range of 80° C. to 100° C.; for a periodof 18 h; to provide a compound of formula (XXII). Cleavage of theprotecting group on a compound of formula (XXII) is achieved accordingto procedures known to one skilled in the art. For example, acidicconditions such as TFA/DCM, HCl/Dioxane, and the like, provides acompound of formula (XXIII).

According to SCHEME 8, tert-butyl3-methyl-2,5-dihydro-1H-pyrrole-1-carboxylate is deprotected employingconditions previously described to provide3-methyl-2,5-dihydro-1H-pyrrole. 3-Methyl-2,5-dihydro-1H-pyrroleundergoes reductive amination with benzaldehyde using a reducing agentsuch as sodium triacetoxyborohydride, sodium cyanoborohydride, and thelike; in a suitable solvent such as DCM, and the like; to afford1-benzyl-3-methyl-2,5-dihydro-1H-pyrrole.

According to SCHEME 9, a compound of formula (XXIV), where R³ issuitably substituted aryl group, is condensed with4-methylbenzenesulfonhydrazide; in a suitable solvent such as THF, MeOH,and the like; at room temperature for a period of 1-16 h to provide acompound of formula (XXV). A compound of formula (XXV) is treated with abase such as sodium hydride (NaH), sodium hydroxide, and the like; withor without an additive such as benzyltriethylammonium chloride; in asolvent such as THF, toluene, and the like; at temperatures ranging fromroom temperature to 80° C.; for a period of 1-2 h; and the resultingaryldiazo intermediate is reacted under the Charette modification ofSimmons-Smith cyclopropanation conditions with a compound of formula(XXVI), where R^(c) is H or CH₃; with a suitable catalyst such as zincdiiodide, and the like; in a solvent such as DCM, and the like; at roomtemperature; over 1-16 h; to provide a compound of formula (XXVII). Acompound of formula (XXVIII) is prepared by hydrogenolysis of a compoundof formula (XXVII) under an atmosphere of H₂; in the presence of acatalyst such as Pd/C, and the like; in a suitable solvent such asEtOAc, EtOH, MeOH, THF, and the like. Alternatively, a compound offormula (XXVIII) is prepared by deprotecting a compound of formula(XXVII) using an acylating agent such as 1-chloroethylcarbonochloridate;a base such as TEA, and the like; in a solvent such as DCM, and thelike; followed by stirring in a solvent such as MeOH and the like; at atemperature of 80° C.

According to SCHEME 10, a compound of formula (XXIV), where R³ issuitably substituted aryl group, is condensed with hydrazinemonohydrate; at room temperature for a period of 30 min; to provide acompound of formula (XXIX). A compound of formula (XXIX) is treated withmanganese(IV) oxide; in a suitable solvent such as 1,4-dioxane, and thelike; at room temperature; for a period of 2 h; and the resultingintermediate is reacted with N-benzylmaleimide at a temperature of 100°C. for a period of 16 h to provide a compound of formula (XXXI). Underconditions known to one skilled in the art, a compound of formula (XXXI)is reduced with a reducing agent such as NaBH₄, LiAlH₄, LiBH₄,diisobutylaluminum hydride (DIBAL-H), and the like; in a suitablesolvent such as THF, MeOH, EtOH, and the like; at temperatures rangingfrom −78 to 0° C.; for a period of 30 min to 16 h; to provide a compoundof formula (XXVII), where R^(c) is H. A compound of formula (XXVII) issubjected to hydrogenolysis employing conditions previously described toprovide a compound of formula (XXVIII).

According to SCHEME 11, pinacol(dichloromethyl)boronate is reacted withsodium iodide (NaI); in a suitable solvent such as acetone, and thelike; at a temperature of 55° C. over a period of 72 h to providepinacol(diiodomethyl)boronate. Either pinacol(diiodomethyl)boronate orpinacol(dichloromethyl)boronate is reacted with a pre-stirred mixture ofchromium(II) chloride; N,N,N′,N′-tetramethylethylenediamine (TMEDA); ina suitable solvent such as THF, and the like; before adding tert-butyl2,5 dihydro-1H-pyrrole-1-carboxylate and heating to 50° C. for 20 h toprovide tert-butyl(1R,5S,6s)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate.tert-Butyl(1R,5S,6s)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylateis reacted under Suzuki coupling conditions with a suitably substitutedaryl halide of formula (XXXII), where R³ is a suitably substituted arylgroup and X is either iodo or bromo; a palladium catalyst such asbis(triphenylphosphine)palladium(II) dichloride, CataCXium A Pd G₃, andthe like; a suitable base such a potassium phosphate, Cs₂CO₃, and thelike; in a suitable solvent such as dioxane, water, EtOH, or a mixturethereof; to provide a compound of formula (XXXIV). A compound of formula(XXXIV) is submitted to deprotection conditions as previously describedto a compound of formula (XXVIII), where R_(c) is H.

According to SCHEME 12, a compound of Formula (I), where R¹ is hydrogenand X is CH₂ or O, is prepared by conventional amide bond formingtechniques such as coupling reactions which are well known to thoseskilled in the art (such as HATU(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate), BOP(benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate), or conversion of the acid to an acid chloride).For example, reaction of a compound of formula (XXVIII), where R_(c) isH or CH₃, and R³ is as defined in claim 1; or a compound of formula(XXIII), where n is each independently 1 or 2; is reacted with asynthetically accessible suitably substituted carboxylic acid of formula(XXXV) (which includes a compound of formula (XI)), where the acid isactivated with an appropriate activating reagent, for example acarbodiimide, such as N,N′-dicyclohexylcarbodiimide (DCC) or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC or EDCI)optionally in the presence of hydroxybenzotriazole (HOBt) and/or acatalyst such as 4-dimethylaminopyridine (DMAP); ahalotrisaminophosphonium salt such as(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP), or bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP®);a suitable pyridinium salt such as 2-chloro-1-methyl pyridiniumchloride; or another suitable coupling agent such asN,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uroniumhexafluorophosphate (HBTU),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU),2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P®)and the like. Coupling reactions are conducted in a suitable solventsuch as DCM, THF, DMF and the like, optionally in the presence of atertiary amine such as N-methylmorpholine, N-ethyldiisopropylamine(DIPEA), or triethylamine (TEA), at a temperature ranging from 0° C. tort, to provide a compound of Formula (I).

A compound of Formula (I) where R³ is phenyl substituted withC(CH₃)₂CO₂CH₃ is reacted under hydrolysis conditions known to oneskilled in the art, for example, utilizing a base such as LiOH.H₂O, andthe like; in a suitable solvent such as water, 1,4-dioxane, and thelike; at room temperature for up to 16 hours to provide a compound ofFormula (I) where R³ is phenyl substituted with C(CH₃)₂CO₂H.

A compound of Formula (I), where Y is

where R_(c) is H, and R³ is phenyl substituted with I and tert-butyl, isreacted in an HCube® under continuous-flow deuteration conditionsutilizing D₂O as the source for deuterium gas; a suitable catalyst suchas Pd/C and the like; in a suitable solvent such as CD₃OD,tetrahydrofuran-d₈, or a mixture thereof; to provide(2s,4S)-2-((1R,5S,6S)-6-(3-(tert-butyl)phenyl-5-D)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

According to SCHEME 13, a suitably substituted, commercially availablearyl bromide of formula (XXXVI), where R³ is phenyl substituted with oneor two members each independently selected from F or C₁₋₄alkyl; isreacted with a base, such as n-BuLi, and the like; a formyl source suchas DMF and the like; in a solvent such as THF, and the like; for aperiod of 3 hours at a temperature of −70° C. to provide a compound offormula (XXIV).

A compound of formula (XXIV), where R³ is phenyl substituted with one ortwo members each independently selected from Br or C₁₋₄alkyl; is reactedin a metal-mediated cross coupling reaction to provide a compound offormula (XXIV), where R³ is phenyl substituted with one or two memberseach independently selected from C₃₋₆cycloalkyl or C₁₋₄alkyl. Forexample, a compound of formula (XXIV), where R³ is substituted with Brand CH₃; is reacted with a commercially available suitably substitutedboronic acid such as cyclopropylboronic acid; in the presence of apalladium catalyst such as Pd(OAc)₂,bis(triphenylphosphine)palladium(II)chloride (PdCl₂(PPh₃ ⁾ ₂),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(PdCl₂(dppf)), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄),2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (RuPhos-Pd-G3), and the like; a phosphine ligand suchas PPh₃; base such as potassium phosphate, Na₂CO₃, Cs₂CO₃, and the like;in a suitable solvent such as ACN, water, 1,4-dioxane, toluene, or amixture thereof; at a temperature ranging from 70° C.-120° C.; for aperiod ranging from 2 h to 48 h, using conventional or microwaveheating, to provide a compound of formula (XXIV), where R³ is phenylsubstituted with cyclopropyl and CH₃.

According to SCHEME 14, 1-iodo-3-methyl-benzene is treated withtert-butyl chloride and aluminum chloride; for a period of 1 h; attemperatures ranging from 0° C. to rt; to provide1-tert-butyl-3-iodo-5-methylbenzene. 1-tert-Butyl-3-iodo-5-methylbenzeneis treated with (PhCO₂)₂; and NBS; in a suitable solvent such as carbontetrachloride; at reflux temperature; for a period of 16 hours; toprovide 1-(bromomethyl)-3-tert-butyl-5-iodobenzene.1-(Bromomethyl)-3-tert-butyl-5-iodobenzene is oxidized under Kornblumconditions; in a suitable solvent such as DMSO, and the like; attemperatures ranging from rt to 100° C.; to provide a compound offormula (XXIV) where R³ is phenyl substituted with iodo and tert-butyl.

According to SCHEME 15,(1R,5S,6s)-3-benzyl-6-(3-bromophenyl)-3-azabicyclo[3.1.0]hexane isreacted with ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane;ZnF₂; a suitable catalyst such as Pd₂(dba)₃, and the like; and a ligandsuch as P(t-Bu)₃, and the like; at a temperature of 90° C. over 6 hoursto provide a compound of formula (XXVII), where R_(c) is H and R³ isphenyl substituted with C(CH₃)₂CO₂CH₃. A compound of formula (XXVIII),where R³ is phenyl substituted with C(CH₃)₂CO₂CH₃ is prepared from acompound of formula (XXVII), where R_(c) is H and R³ is phenylsubstituted with C(CH₃)₂CO₂CH₃ employing hydrogenolysis conditions knownto one skilled in the art or as previously described.

A compound of formula (XXVIII), where R_(c) is H and R³ is phenylsubstituted with C(CH₃)₂CH₂OH, is prepared in two steps from a compoundof formula (XXVII), where R_(c) is H and R³ is phenyl substituted withC(CH₃)₂CO₂CH₃. In a first step, a compound of formula (XXVII), whereR_(c) is H and R³ is phenyl substituted with C(CH₃)₂CO₂CH₃ is reducedemploying conditions known to one skilled in the art. For example, acompound of formula (XXVII), where R_(c) is H and R³ is phenylsubstituted with C(CH₃)₂CO₂CH₃ is reduced with a suitable reducing agentsuch as NaBH₄, LiAlH₄, LiBH₄, diisobutylaluminum hydride (DIBAL-H), andthe like; in a suitable solvent such as tetrahydrofuran (THF), methanol(MeOH), ethanol (EtOH), and the like; at temperatures ranging from −78to 0° C.; for a period of 30 min to 16 h. Subsequent hydrogenolysis,employing conditions as previously described, to provides a compound offormula (XXVIII), where R_(c) is H and R³ is phenyl substituted withC(CH₃)₂CH₂OH.

Alternately,(racemic)-(1*R,5*S,6*R)-3-benzyl-6-(4-bromo-3-(trifluoromethoxy)phenyl)-1-methyl-3-azabicyclo[3.1.0]hexaneis reacted in a metal-mediated cross coupling reaction with acommercially available suitably substituted borane, such as2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane; in the presence of apalladium catalyst such as Pd(OAc)₂,bis(triphenylphosphine)palladium(II)chloride (PdCl₂(PPh₃)₂),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(PdCl₂(dppf)), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄),2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (RuPhos-Pd-G3), and the like; a phosphine ligand suchas PPh₃; base such as potassium phosphate, Na₂CO₃, Cs₂CO₃, and the like;in a suitable solvent such as ACN, water, 1,4-dioxane, toluene, or amixture thereof; at a temperature ranging from 70° C.-120° C.; for aperiod ranging from 2 h to 48 h, using conventional or microwaveheating, to provide a compound of formula (XXVII), where R³ is phenylsubstituted with OCF₃ and CH₃. A compound of formula (XXVII), where R³is phenyl substituted with OCF₃ and CH₃, is reacted under hydrogenolysisconditions as previously described, to provide a compound of formula(XXVIII), where R_(c) is H.

According to SCHEME 16, a compound of formula (XXIX), where R³ is asdescribed in claim 1, is treated with tert-butyl2,5-dioxo-2,5-dihydro-1H-pyrrole-1-carboxylate, employing conditionspreviously described in SCHEME 10, to provide a compound of formula(XXXIV). A compound of formula (XXVIII), is prepared in two steps from acompound of formula (XXXIV). In a first step, deprotection of thetert-butyl carbamate protecting group is achieved employing conditionsknown to one skilled in the art, or as previously described. Subsequentreduction of is achieved employing conditions known to one skilled inthe art, for example, reduction with a suitable reducing agent such asNaBH₄, LiAlH₄, LiBH₄, diisobutylaluminum hydride (DIBAL-H), and thelike; with an additive such as BF₃.OEt₂; in a suitable solvent such asTHF, MeOH, EtOH, and the like; at temperatures ranging from 0 to 50° C.;for a period of 30 min to 16 h; to provide a compound of formula(XXVIII), where R_(c) is H.

Compounds of Formula (I) may be converted to their corresponding saltsusing methods known to one of ordinary skill in the art. For example, anamine of Formula (I) is treated with trifluoroacetic acid, HCl, orcitric acid in a solvent such as Et₂O, CH₂Cl₂, THF, MeOH, chloroform, orisopropanol to provide the corresponding salt form. Alternately,trifluoroacetic acid or formic acid salts are obtained as a result ofreverse phase HPLC purification conditions. Crystalline forms ofpharmaceutically acceptable salts of compounds of Formula (I) may beobtained in crystalline form by recrystallization from polar solvents(including mixtures of polar solvents and aqueous mixtures of polarsolvents) or from non-polar solvents (including mixtures of non-polarsolvents).

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.

Compounds prepared according to the schemes described above may beobtained as single forms, such as single enantiomers, by form-specificsynthesis, or by resolution. Compounds prepared according to the schemesabove may alternately be obtained as mixtures of various forms, such asracemic (1:1) or non-racemic (not 1:1) mixtures. Where racemic andnon-racemic mixtures of enantiomers are obtained, single enantiomers maybe isolated using conventional separation methods known to one ofordinary skill in the art, such as chiral chromatography,recrystallization, diastereomeric salt formation, derivatization intodiastereomeric adducts, biotransformation, or enzymatic transformation.Where regioisomeric or diastereomeric mixtures are obtained, asapplicable, single isomers may be separated using conventional methodssuch as chromatography or crystallization.

The following specific examples are provided to further illustrate theinvention and various preferred embodiments.

EXAMPLES

In obtaining the compounds described in the examples below and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt) under a nitrogen atmosphere. Where solutions were“dried,” they were generally dried over a drying agent such as Na₂SO₄ orMgSO₄. Where mixtures, solutions, and extracts were “concentrated”, theywere typically concentrated on a rotary evaporator under reducedpressure. Reactions under microwave irradiation conditions were carriedout in a Biotage Initiator or CEM (Microwave Reactor) Discoverinstrument.

For the reactions conducted under continuous flow conditions, “flowedthrough a LTF-VS mixer” refers to the use of a Chemyx Fusion 100 TouchSyringe Pump that is in line via 1/16″ PTFE tubing to a LTF-VS mixer(Little Things Factory GmbH (http://www.ltf-gmbh.com), unless otherwiseindicated.

Normal-phase silica gel chromatography (FCC) was performed on silica gel(SiO₂) using prepacked cartridges.

Preparative reverse-phase high performance liquid chromatography (RPHPLC) was performed on either:

METHOD A. An Agilent HPLC with an Xterra Prep RP18 column (5 μM, 30×100or 50×150 mm) or an XBridge C18 OBD column (5 μM 30×100 or 50×150 mm),and a mobile phase of 5% ACN in 20 mM NH₄OH was held for 2 min, then agradient of 5-99% ACN over 15 min, then held at 99% ACN for 5 min, witha flow rate of 40 or 80 mL/min.

or

METHOD B. A Shimadzu LC-8A Series HPLC with an Inertsil ODS-3 column (3μm, 30×100 mm, T=45° C.), mobile phase of 5% ACN in H₂O (both with 0.05%TFA) was held for 1 min, then a gradient of 5-99% ACN over 6 min, thenheld at 99% ACN for 3 min, with a flow rate of 80 mL/min.

or

METHOD C. A Shimadzu LC-8A Series HPLC with an XBridge C18 OBD column (5μm, 50×100 mm), mobile phase of 5% ACN in H₂O (both with 0.05% TFA) washeld for 1 min, then a gradient of 5-99% ACN over 14 min, then held at99% ACN for 10 min, with a flow rate of 80 mL/min.

or

METHOD D. A Gilson HPLC with an XBridge C18 column (5 μm, 100×50 mm),mobile phase of 5-99% ACN in 20 mM NH₄OH over 10 min and then hold at 99ACN for 2 min, at a flow rate of 80 mL/min.

or

METHOD E. An ACCQ Prep HPLC with an XBridge C18 OBD column (5 μM,50×100), mobile phase of 5% ACN in H₂O (both with 0.05% TFA) was heldfor 1 min, then a gradient of 5-95% ACN over 12 min, then held at 95%ACN for 2 min, with a flow rate of 80 mL/min.

Preparative supercritical fluid high performance liquid chromatography(SFC) was performed on either on a Jasco preparative SFC system, an APS1010 system from Berger instruments, or a SFC-PICLAB-PREP 200 (PICSOLUTION, Avignon, France). The separations were conducted at 100 to 150bar with a flow rate ranging from 40 to 60 mL/min. The column was heatedto 35 to 40° C.

SFC Method: SFC-Lux Cellulose-1, Column Phenomenex Lux Cellulose-1150×4.6 mm, 5 μm, Isocratic mode: 40% Methanol+0.1% Diethylamine and 60%CO₂)

Mass spectra (MS) were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in positive mode unless otherwiseindicated. Calculated (calcd.) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker modelDRX spectrometers. Definitions for multiplicity are as follows:s=singlet, d=doublet, t=triplet, q=quartet, p=pentet, hept=heptet,dd=doublet of doublets, dt=doublet of triplets, dq=double of quartets,dp=doublet of pentets, td=triplet of doublets, tt=triplet of triplets,ddd=doublet of doublet of doublets, m=multiplet, br=broad. It will beunderstood that for compounds comprising an exchangeable proton, saidproton may or may not be visible on an NMR spectrum depending on thechoice of solvent used for running the NMR spectrum and theconcentration of the compound in the solution.

Chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoftCorp., Cambridge, Mass.) or OEMetaChem V1.4.0.4 (Open Eye).

Compounds designated as *R or *S are enantiopure compounds where theabsolute configuration was not determined.

Intermediate 1: tert-Butyl 3-nitrocyclobutanecarboxylate

Step A: tert-Butyl 3-hydroxyiminocyclobutanecarboxylate. To a solutionof tert-butyl 3-oxocyclobutane-1-carboxylate (100 g, 588 mmol) inethanol (EtOH) (1.8 L) was added sodium acetate (NaOAc) (192 g, 2340mmol) and hydroxylamine hydrochloride (81 g, 1166 mmol). The reactionmixture was stirred at reflux for 4 h then filtered through a pad ofCelite® and the pad was washed with EtOH. The combined filtrates wereevaporated and the residue was taken up in ethyl acetate (EtOAc) andwashed with water and brine. The organic layer was dried over magnesiumsulfate, filtered, and concentrated to give the title compound (108 g,584 mmol, 99%) as a white solid. MS (ESI): mass calcd. for C₉H₁₅NO₃185.1; m/z found, 186.2 [M+H]⁺.

Step B: tert-Butyl 3-nitrocyclobutanecarboxylate. To a suspension ofurea hydrogen peroxide (164 g, 1.74 mol) in acetonitrile (MeCN) (1 L)was added a solution of trifluoroacetic anhydride (TFAA) (245 mL, 1.75mol) in MeCN (500 mL) dropwise over 1 h at −10° C. The reaction mixturewas stirred at room temperature for 1 h. The solution was added to asolution of tert-butyl 3-hydroxyiminocyclobutanecarboxylate (108 g,0.584 mol) and sodium phosphate dibasic (911 g, 6.42 mol) in MeCN (1 L)dropwise over 30 min at 80° C. The reaction mixture was stirred at 80°C. for 30 min then filtered through a pad of Celite® and the pad waswashed with MeCN. The combined filtrates were diluted with EtOAc. Themixture was washed with water and brine. The organic layer was driedover magnesium sulfate, filtered and evaporated. The residue waspurified by flash column chromatography (FCC) on silica (0-20% EtOAc inheptane) to give the title compound (89.6 g, 445 mmol, 76%) as a yellowoil as a 1.3:1 mixture of cis/trans isomers. Compound does not ionizewith ESI LCMS.

Intermediate 2: Ethyl 3-nitrocyclobutanecarboxylate

The title compound was prepared in a manner analogous to Intermediate 1using ethyl 3-oxocyclobutane-1-carboxylate instead of tert-butyl3-oxocyclobutane-1-carboxylate in Step A. Compound does not ionize withESI⁺ LCMS. ¹H NMR (300 MHz, Chloroform-d) δ 5.02-4.70 (m, 1H), 4.20 (q,J=7.2 Hz, 2H), 3.04-2.71 (m, 5H), 1.29 (t, J=7.0 Hz, 3H).

Intermediate 3: (2s,4s)-6-Oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylicacid

Step A: tert-Butyl(1s,3s)-3-(hydroxymethyl)-3-nitrocyclobutane-1-carboxylate. To asolution of tert-butyl 3-nitrocyclobutanecarboxylate (Intermediate 1,89.6 g, 445 mmol) in MeCN (1 L) was added formaldehyde (37 wt % inwater, 73 mL, 971 mmol). To the reaction mixture was added triethylamine(TEA) (62 mL, 444 mmol) dropwise at 0° C. and the reaction was stirredat room temperature for 2 h. The reaction mixture was evaporated and theresidue was purified by FCC on silica (0-25% EtOAc in heptane) to givethe title compound (38.25 g, 165 mmol, 37%) as a white powder. MS (ESI):mass calcd. for C₁₀H₁₇NO₅ 231.2; m/z found, 254.1 [M+Na]⁺.trans-tert-Butyl 3-(hydroxymethyl)-3-nitro-cyclobutanecarboxylate wasformed, but not isolated.

Step B: tert-Butyl(1s,3s)-3-amino-3-(hydroxymethyl)cyclobutane-1-carboxylate. To asolution of tert-butyl(1s,3s)-3-(hydroxymethyl)-3-nitro-cyclobutanecarboxylate (38.2 g, 165mmol) in EtOAc (600 mL) was added 10% palladium on carbon (Pd/C) (1.9g). The reaction mixture was stirred at 50° C. for 1 h under hydrogen(H₂) (10 bar). The reaction mixture was filtered through a pad ofCelite®. To the filtrate was added 10% Pd/C (1.9 g). The reactionmixture was stirred at 50° C. for 2 h under H₂ (10 bar). The reactionmixture was filtered through a pad of Celite® and the Celite® was washedwith EtOAc. The combined filtrates were evaporated and the residue wastriturated with diethyl ether (Et₂O) to give the title compound (18.6 g,92.4 mmol, 55%) as a white powder. MS (ESI): mass calcd. for C₁₀H₁₉NO₃201.1; m/z found, 202.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 5.26-3.98(m, 1H), 3.74-2.94 (m, 4H), 2.70-2.57 (m, 1H), 2.20-2.07 (m, 2H),1.97-1.82 (m, 2H), 1.39 (s, 9H).

Step C: tert-Butyl(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate. To a solutionof tert-butyl (1s,3s)-3-amino-3-(hydroxymethyl)cyclobutane-1-carboxylate(18.6 g, 92.4 mmol) in tetrahydrofuran (THF) (300 mL) was added TEA (26mL, 186 mmol). To the mixture was added a solution of triphosgene (9.6g, 32.4 mmol) in THF (200 mL) dropwise at −10° C. and stirred at roomtemperature for 1 h. The reaction mixture poured into saturated sodiumbicarbonate (600 mL) and the mixture was extracted with EtOAc. Thecombined organic layers were dried over magnesium sulfate, filtered, andevaporated. The residue was triturated with Et₂O to give the titlecompound (17.7 g, 77.9 mmol, 84%) as a white powder. MS (ESI): masscalcd. for C₁₁H₁₇NO₄ 227.1; m/z found, 228.2 [M+H]⁺.

Step D: (2s,4s)-6-Oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid. Totrifluoroacetic acid (TFA) (180 mL, 235 mmol) was added tert-butyl(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate (17.7 g, 77.9mmol) in portions at 0° C. The reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was evaporated and the residuewas triturated with Et₂O to afford the title compound (12.9 g, 75.4mmol, 96%) as a white powder. MS (ESI): mass calcd. for C₇H₉NO₃ 171.0;m/z found, 172.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.26 (br s, 1H),8.08 (s, 1H), 4.34 (s, 2H), 2.79-2.66 (m, 1H), 2.43-2.29 (m, 4H).

Intermediate 4: (2r,4s)-6-Oxo-5-azaspiro[3.4]octane-2-carboxylic acid

Step A: Ethyl(1r,3s)-3-(3-methoxy-3-oxopropyl)-3-nitrocyclobutane-1-carboxylate. To asolution of ethyl 3-nitrocyclobutanecarboxylate (Intermediate 2, 16.6 g,95.6 mmol) in MeCN (145 mL) was added methyl acrylate (10.3 mL, 114mmol). To the reaction mixture was added1,8-diazabicyclo[5.4.0]undec-7-ene (7.1 mL, 47.6 mmol) dropwise at 0° C.and the reaction mixture was stirred at 0° C. for 1 h. The reactionmixture was diluted with saturated ammonium chloride and EtOAc and thelayers were separated. The organic layer was dried over magnesiumsulfate, filtered and evaporated. The residue was purified by FCC onsilica (0-15% EtOAc in heptane) to give the title compound (13.6 g, 52.7mmol, 55%) as a colorless liquid. MS (ESI): mass calcd. for C₁₁H₁₇NO₆259.1; m/z found, 282.1 [M+Na]⁺. ¹H NMR (300 MHz, Chloroform-d) δ4.17(q, J=7.1 Hz, 2H), 3.70 (s, 3H), 3.12-2.79 (m, 3H), 2.69-2.49 (m, 2H),2.48-2.21 (m, 4H), 1.27 (t, J=7.1 Hz, 3H).

Step B: (2r,4s)-6-Oxo-5-azaspiro[3.4]octane-2-carboxylic acid. To asolution of ethyl(1r,3s)-3-(3-methoxy-3-oxopropyl)-3-nitrocyclobutane-1-carboxylate (13.6g, 52.5 mmol) in methanol (MeOH) (133 mL) was added nickel(II) chloridehexahydrate (12.5 g, 52.6 mmol). To the reaction mixture was addedsodium borohydride (NaBH₄) (10 g, 264 mmol) in small portions at −10° C.and the reaction mixture was stirred at 0° C. for 1 h. To the reactionmixture was added aqueous potassium carbonate (47 mL, 141 mmol, 3 M)dropwise at 0° C. (pH 10) and the reaction mixture was stirred at 0° C.for 1 h. The reaction mixture was filtered through a pad of Celite® andthe pad was washed with EtOH. The combined filtrates were evaporated.The residue was purified by FCC on silica eluting withchloroform:methanol:acetic acid (100:0:0→9:1:1) to give the titlecompound (4.8 g, 28.2 mmol, 53%) as an off-white powder. MS (ESI): masscalcd. for C₈H₁₁NO₃ 169.1; m/z found, 170.1 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 7.97 (br s, 1H), 4.01-2.94 (m, 1H), 2.82-2.65 (m, 1H),2.36-2.01 (m, 8H).

Intermediate 5: Potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate

Step A: tert-Butyl1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate.In a flask under N₂ was placed anhydrous DCM (62 mL) followed bydiethylzinc (68 mL, 1 M in hexanes, 68 mmol). The mixture was cooled to−40° C. and a solution of diiodomethane (11 mL, 135 mmol) in DCM (26 mL)was slowly added by addition funnel over 30 min. The reaction was thenallowed to stir at −40° C. for 1 h. At −40° C., a solution of TFA (5.2mL, 68 mmol) in DCM (26 mL) was slowly added over 20 min by additionfunnel. The reaction was warmed to −15° C. and stirred for 1 h. Asolution of tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(2.5 g, 8.5 mmol) in DCM (26 mL) was slowly added by addition funnel tothe reaction mixture. The reaction was allowed to warm overnight withstirring. Over the course of the reaction, the BOC group is cleaved andmust be reinstalled. After stirring overnight, the crude reactionmixture is partially concentrated to one quarter volume. THF (38 mL) isadded followed by di-tert-butyl dicarbonate (9.2 g, 42 mmol), TEA (11.8mL, 85 mmol), and DMAP (0.25 g, 2.1 mmol). The reaction was stirred atroom temperature for 3 h under N₂, after which it was diluted with EtOAcand washed with sat. NaHCO₃. The organic layer was dried over MgSO₄,filtered, and concentrated under reduced pressure to afford the crudeproduct as red-brown oil. The crude product was purified by FCC onsilica (0-10% EtOAc in heptane). The desired fractions were collectedand concentrated under vacuum to yield a pale yellow solid (1.0 g, 38%yield). MS (ESI): mass calcd. for C₁₆H₂₈BNO₄ 309.2; m/z found, 254.0[M+2H-tBu]⁺. ¹H NMR (300 MHz, CDCl₃) δ 3.67-3.27 (m, 4H), 1.66-1.55 (m,1H), 1.41 (s, 9H), 1.22 (s, 12H), 0.95 (dd, J=7.2, 4.1 Hz, 1H),0.44-0.35 (m, 1H).

Step B: Potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate.tert-Butyl1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(1 g, 3.2 mmol) was dissolved in MeOH (20 mL), treated with KHF₂ (1.8 g,22.6 mmol) and stirred at 65° C. for 16 h. The reaction mixture wascooled to room temperature and concentrated under reduced pressure. Theresulting residue was triturated with 20% Et₂O in heptane (13 mL) for 10min. The precipitate was collected by filtration and rinsed with Et₂O.The precipitate was dissolved in hot ACN (100 mL) and filtered to removeKHF₂. The filtrate was collected and concentrated under reduced pressureto afford the title compound as a white solid (830 mg, 88% yield). MS(ESI): mass calcd. for C₁₀H₁₆BF₃KNO₂ 289.1; m/z found, 172.1[M−tBu—KF]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.30 (s, 1H), 3.19-3.05 (m,3H), 1.35 (s, 9H), 0.94 (s, 1H), 0.39-0.29 (m, 1H), −0.41 (s, 1H).

Intermediate 6: Potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate

The title compound was prepared in a manner analogous to Intermediate 5using tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylateinstead of tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylatein Step A. MS (ESI): mass calcd. for C₁₁H₁₈BF₃KNO₂ 303.1; m/z found,186.0 [M−tBu—KF]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.51-3.36 (m, 2H),3.11-3.02 (m, 1H), 2.89 (s, 1H), 1.81-1.69 (m, 1H), 1.36 (s, 9H),1.31-1.21 (m, 1H), 0.63-0.53 (m, 1H), 0.26-0.16 (m, 1H), −0.29 (s, 1H).

Intermediate 7: Potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-1-yl)trifluoroborate

The title compound was prepared in a manner analogous to Intermediate 5using tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylateinstead of tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylatein Step A. MS (ESI): mass calcd. for C₁₁H₁₈BF₃KNO₂ 303.1; m/z found,186.0 [M−tBu—KF]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 3.66-3.38 (m, 2H), 3.19(s, 1H), 2.72 (s, 1H), 1.76-1.51 (m, 2H), 1.39-1.36 (m, 9H), 0.60 (s,1H), 0.23-0.14 (m, 1H), −0.35 (s, 1H).

Intermediate 8: 4-Bromo-1-methyl-2-(trifluoromethoxy)benzene

4-Bromo-2-(trifluoromethoxy)iodobenzene (321 μL, 1.9 mmol) added to asolution of tetrakis(triphenylphosphine)palladium (220 mg, 0.19 mmol) inanhydrous THF (90 mL) under N₂. Dimethylzinc solution (1M in hexane,2.86 mL) was added dropwise. The mixture was stirred at 50° C. for 3 h.The reaction mixture was partially concentrated under vacuum (product isvolatile) and filtered through silica gel eluting with pentane. Theresult was partially concentrated to yield the title compound (486 mg,crude). This was used without further purification in subsequent steps.MS (ESI): mass calcd. for C₈H₆BrF₃O 254.0; m/z found, 253.9 [M]⁺. ¹H NMR(300 MHz, CDCl₃) δ 7.39-7.30 (m, 2H), 7.13 (d, J=8.1 Hz, 1H), 2.27 (s,3H).

Intermediate 9: 1-Benzyl-3-methyl-2,5-dihydro-1H-pyrrole

To a solution of tert-butyl3-methyl-2,5-dihydro-1H-pyrrole-1-carboxylate (250 mg, 1.36 mmol) in DCM(4 mL) was added TFA (1 mL), and the reaction stirred at roomtemperature for 40 min. The mixture was concentrated in vacuo, theresidue re-dissolved in DCM (2.6 mL), and benzaldehyde (0.14 mL, 1.36mmol) added. After stirring at room temperature for 1 h, sodiumtriacetoxyborohydride (578 mg, 2.73 mmol) was added portion-wise and thereaction allowed to stir overnight. The mixture was carefully quenchedwith sat. aq. NaHCO₃ and the aqueous phase extracted with DCM. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and the filtrate concentrated under reduced pressure. Thecrude residue was purified by FCC on silica (0-10% of a 2M NH₃/MeOHsolution in DCM) to afford the title compound as a brown oil (104 mg,44%). MS (ESI): mass calcd. for C₁₂H₁₅N, 173.1; m/z found, 174.1 [M+H]⁺.¹H NMR (600 MHz, Chloroform-d) δ 7.37-7.34 (m, 2H), 7.33-7.30 (m, 2H),7.25 (d, J=10.2 Hz, 1H), 5.39-5.36 (m, J=1.8 Hz, 1H), 3.80 (s, 2H),3.48-3.44 (m, 2H), 3.37-3.34 (m, 2H), 1.73-1.69 (m, 3H).

Intermediate 10: 3-Isobutylbenzaldehyde

n-BuLi (2.2 mL, 2.5 M in hexane, 5.5 mmol) was added dropwise to a −70°C. solution of 1-bromo-3-isobutylbenzene (1.0 g, 4.7 mmol) in anhydrousTHF (15 mL). The resultant mixture was stirred at −70° C. for 1 hourbefore being treated with DMF (0.36 mL, 4.7 mmol). The mixture wasstirred at −70° C. for 2 hours before being quenched with water andextracted with ethyl acetate. The combined organic extracts were driedover anhydrous Na₂SO₄, filtered, and concentrated under reduced pressureto give the title compound (800 mg, crude), as a colorless oil. ¹H NMR(400 MHz, DMSO-d₆) δ 9.99 (s, 1H), 7.77-7.67 (m, 2H), 7.54-7.49 (m, 2H),2.55 (d, J=7.3 Hz, 2H), 1.92-1.80 (m, 1H), 0.86 (d, J=6.5 Hz, 6H).

Intermediate 11: 3-Ethyl-4-fluorobenzaldehyde

The title compound was prepared in a manner analogous to Intermediate 10using 4-bromo-2-ethyl-1-fluorobenzene instead of1-bromo-3-isobutylbenzene. ¹H NMR (400 MHz, CDCl₃) δ 9.84-9.79 (m, 1H),7.68-7.64 (m, 1H), 7.63-7.58 (m, 1H), 7.07-7.00 (m, 1H), 2.62 (q, J=7.5Hz, 2H), 1.15 (t, J=7.6 Hz, 3H).

Intermediate 12: 4-Cyclopropyl-2-methylbenzaldehyde

4-Bromo-2-methylbenzaldehyde (1.5 g, 7.54 mmol) was taken up in1,4-dioxane (15 mL) and water (6 mL) under a nitrogen atmosphere. Tothis was added cyclopropylboronic acid (1.6 g, 18.8 mmol), Cs₂CO₃ (5.4g, 16.6 mmol), and Pd(dppf)Cl₂ (0.92 g, 1.13 mmol). The mixture wasstirred at 90° C. for 16 h before cooling to rt. The mixture wasfiltered through Celite® then diluted with diethylether and washed withwater and brine. The organic phase was dried over MgSO₄, filtered, andconcentrated under reduced pressure. The crude product was purified byFCC (0-40% DCM in pentane) to provide the title compound as a colorlessoil (1.2 g, 96% yield). ¹H NMR (300 MHz, CDCl₃) δ 10.18 (s, 1H), 7.68(d, J=8.0 Hz, 1H), 7.00 (d, J=7.9 Hz, 1H), 6.92 (s, 1H), 2.63 (s, 3H),2.00-1.82 (m, 1H), 1.05 (dd, J=7.2, 5.4 Hz, 2H), 0.89-0.67 (m, 2H).

Intermediate 13: 3-tert-Butyl-5-iodobenzaldehyde

Step A: 1-tert-Butyl-3-iodo-5-methylbenzene. tert-Butyl chloride (178 g,1.93 mol) and 1-iodo-3-methyl-benzene (280 g, 1.28 mol) were placedunder Na and cooled to 0° C. To this was added aluminum chloride (514 g,3.85 mol) and the resulting solution was allowed to warm to rt andstirred for 1 h. The reaction was diluted with DCM and purified by FCC(0-2% EtOAc in ether) to provide the title compound as a colorless oil(202 g, 57% yield).

Step B: 1-(Bromomethyl)-3-tert-butyl-5-iodobenzene.1-tert-Butyl-3-iodo-5-methylbenzene (202 g, 737 mmol), CCl₄ (3.0 L), and(PhCO₂)₂ (8.9 g, 36.8 mmol) were combined under Na and heated to reflux.To this was added NBS (262 g, 1.47 mol) and the resulting solution washeated at reflux overnight. The reaction mixture was cooled to roomtemperature, diluted with H₂O, and extracted with DCM. The combinedorganic layers were washed with sat. aq. NaHCO₃, dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by FCC (0-2% EtOAc in ether) to provide thetitle compound as a yellow oil (220 g, 85% yield).

Step C: 3-tert-Butyl-5-iodobenzaldehyde.1-(Bromomethyl)-3-tert-butyl-5-iodobenzene (220 g, 625 mmol) was takenup in DMSO (2.2 L) under N₂ and stirred for 4 h at 100° C. The reactionmixture was cooled to room temperature, quenched with water, andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified byFCC (0-2% EtOAc in ether) to provide the title compound as a white solid(100 g, 56% yield). MS (ESI): mass calcd. for C₁₁H₁₃IO, 288.0; m/zfound, 288.1 [M]⁺.

Example 1:(rac)-(2s,4s)-2-(1-(p-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

1-(p-Tolyl)-3-azabicyclo[3.1.0]hexane (20 mg, 0.115 mmol) and(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 20 mg, 0.115 mmol) were taken up in DMF (0.6 mL). DIPEA(60 μL, 0.346 mmol) and HATU (50 mg, 0.127 mmol) were added and thereaction was stirred at rt for 16 h. The reaction mixture was filteredthrough a PTFE filter with MeOH and purified via reverse phase HPLC(5-95% ACN in 20 mM NH₄OH in water) to afford the title compound (30 mg,80% yield). MS (ESI): mass calcd. for C₁₉H₂₂N₂O₃, 326.2; m/z found,327.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.10 (qd, J=8.2, 3.5 Hz,4H), 6.54 (d, J=22.4 Hz, 1H), 4.36 (d, J=4.2 Hz, 2H), 4.23-3.93 (m, 1H),3.86-3.54 (m, 3H), 2.92-2.81 (m, 1H), 2.71-2.62 (m, 2H), 2.52-2.36 (m,2H), 2.32 (d, J=4.9 Hz, 3H), 1.95-1.79 (m, 1H), 1.18-1.07 (m, 1H), 0.73(dt, J=9.6, 4.7 Hz, 1H).

Example 2:(2s,4*R)-2-((1*S,5*R)-1-(p-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 1 (Stationary phase: Lux Cellulose 4, 5 μm250×21 mm, Mobile phase: 50% MeOH, 50% CO₂). MS (ESI): mass calcd. forC₁₉H₂₂N₂O₃, 326.2; m/z found, 327.2 [M+H]⁺. ¹H NMR (500 MHz,Chloroform-d) δ 7.15-7.10 (m, 2H), 7.12-7.05 (m, 2H), 6.27 (d, J=20.1Hz, 1H), 4.35 (d, J=5.3 Hz, 2H), 4.23-3.93 (m, 1H), 3.85-3.55 (m, 3H),2.93-2.83 (m, 1H), 2.69-2.59 (m, 2H), 2.54-2.41 (m, 2H), 2.33 (d, J=4.9Hz, 3H), 1.92-1.83 (m, 1H), 1.16-1.09 (m, 1H), 0.73 (dt, J=11.9, 4.7 Hz,1H).

Example 3:(2s,4*5)-2-((1*R,5*5)-1-(p-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 1 (Stationary phase: Lux Cellulose 4, 5 μm250×21 mm, Mobile phase: 50% MeOH, 50% CO₂). MS (ESI): mass calcd. forC₁₉H₂₂N₂O₃, 326.2; m/z found, 327.2 [M+H]⁺. ¹H NMR (500 MHz,Chloroform-d) δ 7.13 (dd, J=8.0, 4.2 Hz, 2H), 7.12-7.05 (m, 2H), 6.12(d, J=15.9 Hz, 1H), 4.35 (d, J=5.4 Hz, 2H), 4.23-3.93 (m, 1H), 3.84-3.56(m, 3H), 2.93-2.83 (m, 1H), 2.67-2.58 (m, 2H), 2.54-2.41 (m, 2H), 2.33(d, J=4.2 Hz, 3H), 1.92-1.83 (m, 1H), 1.13 (q, J=5.8 Hz, 1H), 0.74 (dt,J=11.6, 4.7 Hz, 1H).

Example 4:(rac)-(2s,4s)-2-(1-Phenyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 1 using1-phenyl-3-azabicyclo[3.1.0]hexane hydrochloride instead of1-(p-tolyl)-3-azabicyclo[3.1.0]hexane. MS (ESI): mass calcd. forC₁₈H₂₀N₂O₃, 312.1; m/z found, 313.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ7.40-7.08 (m, 5H), 4.48 (m, 2H), 4.17-3.96 (m, 1H), 3.93-3.78 (m, 2H),3.61-3.53 (m, 1H), 3.02 (m, 1H), 2.61-2.40 (m, 4H), 2.04-1.93 (m, 1H),1.17-1.10 (m, 1H), 0.75 (m, 1H).

Example 5:(rac)-(2s,4s)-2-(1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: tert-Butyl1-(4-(tert-butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. In avial was combined potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5, 210 mg, 0.73 mmol), CatacXium® A Pd G3 (30 mg, 0.036mmol), 1-bromo-4-(tert-butyl)benzene (250 μL, 1.4 mmol), Cs₂CO₃ (709.9mg, 2.2 mmol), toluene (14 mL) and water (1.4 mL). The resulting mixturewas degassed by bubbling N₂ through the solution for 10 min. Thereaction was then heated to 90° C. for 18 h. Water was added and themixture was extracted with EtOAc. The organic layers were dried overMgSO₄, filtered, and concentrated under reduced pressure. The crudeproduct was purified by FCC on silica (0-10% EtOAc in heptane). Thedesired fractions were collected and concentrated under vacuum to yielda yellow oil (190 mg, 83% yield). MS (ESI): mass calcd. for C₂₀H₂₉NO₂,315.2; m/z found, 260.0 [M+2H−tBu]⁺. ¹H NMR (300 MHz, CDCl₃) δ 7.33 (d,J=8.2 Hz, 2H), 7.11 (t, J=7.7 Hz, 2H), 4.04-3.80 (m, 1H), 3.77-3.44 (m,3H), 1.82-1.74 (m, 1H), 1.46 (s, 9H), 1.31 (s, 9H), 1.12-1.04 (m, 1H),0.86-0.79 (m, 1H).

Step B: 1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane. TFA (0.55mL, 7.2 mmol) was added to a solution of tert-butyl1-(4-(tert-butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (190mg, 0.6 mmol) in DCM (5 mL) at 0° C. The reaction mixture was stirred atrt for 1 h. The reaction mixture was concentrated under vacuum. DCM wasadded and washed with saturated solution of Na₂CO₃. The organic layerswere combined, dried over MgSO₄, filtered, and concentrated under vacuumto yield a yellow oil. The product was used as such in the next stepwithout further purification (129 mg, 0.6 mmol, yield 99%, crude). MS(ESI): mass calcd. for C₁₅H₂₁N, 215.2; m/z found, 216.1 [M+H]⁺.

Step C:(rac)-(2s,4s)-2-(1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.HBTU (297 mg, 0.8 mmol) and DIPEA (0.262 mL, 1.5 mmol) were added to asolution of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 123 mg, 0.722 mmol) in anhydrous DMF (4 mL). Themixture was stirred for 10 min at room temperature, then a solution of1-(4-(tert-butyl)phenyl)-3-azabicyclo[3.1.0]hexane (129 mg, 0.6 mmol) inDMF (1 mL) was added, and the reaction mixture was stirred at roomtemperature for additional 16 h. Saturated NaHCO₃ was added and themixture was extracted with EtOAc. The organic layers were dried overMgSO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified by FCC on silica (0-30% (DCM/MeOH 20:1) in DCM).The desired fractions were collected and concentrated under vacuum. Theresulting solid was triturated with pentane, diisopropyl ether (DIPE),and filtered to yield a beige solid (121.2 mg, 52% yield). MS (ESI):mass calcd. for C₂₂H₂₈N₂O₃, 368.2; m/z found, 369.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.34 (dd, J=8.5, 2.0 Hz, 2H), 7.12 (dd, J=8.3, 5.0 Hz,2H), 6.16 (d, J=6.6 Hz, 1H), 4.36 (d, J=4.5 Hz, 2H), 4.23-3.93 (m, 1H),3.85-3.56 (m, 3H), 2.94-2.83 (m, 1H), 2.68-2.58 (m, 2H), 2.56-2.42 (m,2H), 1.96-1.83 (m, 1H), 1.31 (d, J=1.5 Hz, 9H), 1.19-1.13 (m, 1H),0.78-0.69 (m, 1H).

Example 6:(rac)-(2s,4s)-2-(1-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-3-isopropylbenzene instead of 1-bromo-4-(tert-butyl)benzene inStep A. MS (ESI): mass calcd. for C₂₁H₂₆N₂O₃, 354.2; m/z found, 355.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.21 (m, 1H), 7.11 (t, J=7.9 Hz,1H), 7.06-6.95 (m, 2H), 6.18 (d, J=26.5 Hz, 1H), 4.36 (d, J=3.3 Hz, 2H),4.25-3.94 (m, 1H), 3.87-3.57 (m, 3H), 2.95-2.81 (m, 2H), 2.70-2.59 (m,2H), 2.57-2.40 (m, 2H), 1.98-1.87 (m, 1H), 1.25 (dd, J=6.9, 2.7 Hz, 6H),1.20-1.14 (m, 1H), 0.81-0.72 (m, 1H).

Example 7:(2s,4*5)-2-((1*R,5*5)-1-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 6 (Stationary phase: Whelk O1 SS, 5 μm 250×21mm, Mobile phase: 20% MeOH with 0.2% TEA, 80% CO₂). MS (ESI): masscalcd. for C₂₁H₂₆N₂O₃, 354.2; m/z found, 355.2 [M+H]⁺. ¹H NMR (500 MHz,Chloroform-d) δ 7.23 (dd, J=7.6, 6.5 Hz, 1H), 7.14-7.06 (m, 1H),7.05-6.95 (m, 2H), 6.54 (d, J=45.5 Hz, 1H), 4.36 (d, J=4.1 Hz, 2H),4.25-3.94 (m, 1H), 3.86-3.56 (m, 3H), 2.95-2.82 (m, 2H), 2.71-2.61 (m,2H), 2.52-2.40 (m, 2H), 1.98-1.86 (m, 1H), 1.24 (dd, J=6.9, 4.2 Hz, 6H),1.16 (dt, J=8.5, 4.4 Hz, 1H), 0.76 (dt, J=16.0, 4.8 Hz, 1H).

Example 8:(2s,4*R)-2-((1*S,5*R)-1-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 6 (Stationary phase: Whelk O1 SS, 5 μm 250×21mm, Mobile phase: 20% MeOH with 0.2% TEA, 80% CO₂). MS (ESI): masscalcd. for C₂₁H₂₆N₂O₃, 354.2; m/z found, 355.2 [M+H]⁺. ¹H NMR (500 MHz,Chloroform-d) δ 7.23 (dd, J=7.6, 6.4 Hz, 1H), 7.13-7.07 (m, 1H),7.05-6.95 (m, 2H), 6.51 (d, J=45.8 Hz, 1H), 4.36 (d, J=4.1 Hz, 2H),4.25-3.94 (m, 1H), 3.87-3.57 (m, 3H), 2.93-2.82 (m, 2H), 2.71-2.61 (m,2H), 2.52-2.41 (m, 2H), 1.97-1.84 (m, 1H), 1.24 (dd, J=6.8, 4.1 Hz, 6H),1.18-1.13 (m, 1H), 0.76 (dt, J=15.9, 4.8 Hz, 1H).

Example 9:(rac)-(2s,4s)-2-(1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-4-isopropylbenzene instead of 1-bromo-4-(tert-butyl)benzene inStep A. MS (ESI): mass calcd. for C₂₁H₂₆N₂O₃, 354.2; m/z found, 355.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.16 (m, 2H), 7.14-7.09 (m, 2H),6.13 (d, J=11.4 Hz, 1H), 4.35 (d, J=4.4 Hz, 2H), 4.24-3.92 (m, 1H),3.86-3.55 (m, 3H), 2.94-2.83 (m, 2H), 2.68-2.60 (m, 2H), 2.54-2.41 (m,2H), 1.96-1.83 (m, 1H), 1.24 (dd, J=6.9, 1.5 Hz, 6H), 1.19-1.12 (m, 1H),0.77-0.69 (m, 1H).

Example 10:(2s,4*5)-2-((1*R,5*S)-1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 9 (Stationary phase: Whelk O1 SS, 5 μm 250×21mm, Mobile phase: 15% MeOH:isopropanol (1:1) with 0.2% isopropylamine,85% CO₂). MS (ESI): mass calcd. for C₂₁H₂₆N₂O₃, 354.2; m/z found, 355.3[M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.21-7.15 (m, 2H), 7.15-7.08(m, 2H), 6.36 (d, J=13.1 Hz, 1H), 4.36 (d, J=4.6 Hz, 2H), 4.24-3.92 (m,1H), 3.85-3.56 (m, 3H), 2.95-2.82 (m, 2H), 2.69-2.59 (m, 2H), 2.53-2.40(m, 2H), 1.94-1.84 (m, 1H), 1.23 (dd, J=6.9, 2.0 Hz, 6H), 1.15 (dq,J=8.7, 4.3 Hz, 1H), 0.74 (dt, J=10.8, 4.8 Hz, 1H).

Example 11:(2s,4*R)-2-((1*S,5*R)-1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 9 (Stationary phase: Whelk O1 SS, 5 μm 250×21mm, Mobile phase: 15% MeOH:isopropanol (1:1) with 0.2% isopropylamine,85% CO₂). MS (ESI): mass calcd. for C₂₁H₂₆N₂O₃, 354.2; m/z found, 355.3[M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.18 (dd, J=8.3, 3.1 Hz, 2H),7.15-7.08 (m, 2H), 6.54 (d, J=15.8 Hz, 1H), 4.36 (d, J=4.6 Hz, 2H),4.24-3.92 (m, 1H), 3.85-3.55 (m, 3H), 2.95-2.82 (m, 2H), 2.71-2.60 (m,2H), 2.53-2.40 (m, 2H), 1.94-1.84 (m, 1H), 1.23 (dd, J=6.9, 2.5 Hz, 6H),1.15 (dt, J=9.2, 5.1 Hz, 1H), 0.74 (dt, J=11.0, 4.7 Hz, 1H).

Example 12:(rac)-(2r,4s)-2-(1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-4-isopropylbenzene instead of 1-bromo-4-(tert-butyl)benzene inStep A and using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 4) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₂H₂₈N₂O₂, 352.2;m/z found, 353.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (s, 1H),7.24-7.08 (m, 4H), 4.05-3.56 (m, 3H), 3.47-3.37 (m, 1H), 3.01-2.79 (m,2H), 2.34-2.06 (m, 8H), 2.01-1.86 (m, 1H), 1.17 (dd, J=6.9, 1.1 Hz, 6H),1.06-0.99 (m, 1H), 0.66 (t, J=4.1 Hz, 1H).

Example 13:(rac)-(2r,4s)-2-(1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₃H₃₀N₂O₂, 366.2;m/z found, 367.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.34 (dd, J=8.3, 2.6Hz, 2H), 7.16-7.09 (m, 2H), 6.11 (s, 1H), 4.25-3.89 (m, 1H), 3.88-3.46(m, 3H), 2.98-2.84 (m, 1H), 2.60-2.47 (m, 2H), 2.44-2.32 (m, 4H),2.30-2.18 (m, 2H), 1.95-1.82 (m, 1H), 1.31 (s, 9H), 1.18-1.09 (m, 1H),0.77-0.69 (m, 1H).

Example 14:(2r,4*S)-2-((1*R,5*5)-1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 13 (Stationary phase: Whelk O1 SS, 5 μm 250×21mm, Mobile phase: 15% MeOH:isopropanol (1:1) with 0.2% isopropylamine,85% CO₂). MS (ESI): mass calcd. for C₂₃H₃₀N₂O₂, 366.2; m/z found, 367.3[M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.34 (dd, J=8.2, 3.5 Hz, 2H),7.12 (t, J=8.8 Hz, 2H), 6.17 (s, 1H), 4.25-3.89 (m, 1H), 3.88-3.46 (m,3H), 2.90 (t, J=7.7 Hz, 1H), 2.60-2.45 (m, 2H), 2.37 (d, J=10.3 Hz, 4H),2.21 (q, J=7.1 Hz, 2H), 1.94-1.81 (m, 1H), 1.31 (d, J=1.9 Hz, 9H), 1.14(dt, J=9.1, 5.0 Hz, 1H), 0.74 (dt, J=9.8, 4.6 Hz, 1H).

Example 15:(2r,4*R)-2-((1*S,5*R)-1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 13 (Stationary phase: Whelk O1 SS, 5 μm 250×21mm, Mobile phase: 15% MeOH:isopropanol (1:1) with 0.2% isopropylamine,85% CO₂). MS (ESI): mass calcd. for C₂₃H₃₀N₂O₂, 366.2; m/z found, 367.3[M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.34 (dd, J=8.3, 3.6 Hz, 2H),7.12 (t, J=8.7 Hz, 2H), 6.28-6.17 (m, 1H), 4.25-3.89 (m, 1H), 3.88-3.50(m, 3H), 2.89 (tt, J=8.9, 4.4 Hz, 1H), 2.52 (td, J=11.1, 10.6, 6.3 Hz,2H), 2.37 (d, J=10.3 Hz, 4H), 2.27-2.14 (m, 2H), 1.94-1.81 (m, 1H), 1.31(d, J=2.1 Hz, 9H), 1.14 (p, J=4.9 Hz, 1H), 0.74 (dt, J=10.0, 4.8 Hz,1H).

Example 16:(rac)-(2s,4s)-2-(1-(3-Cyclopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-3-cyclopropylbenzene instead of 1-bromo-4-(tert-butyl)benzene inStep A. MS (ESI): mass calcd. for C₂₁H₂₄N₂O₃, 352.2; m/z found, 353.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.23-7.17 (m, 1H), 6.99-6.94 (m, 1H),6.94-6.89 (m, 2H), 5.96 (d, J=10.5 Hz, 1H), 4.36 (d, J=3.3 Hz, 2H),4.25-3.89 (m, 1H), 3.84-3.55 (m, 3H), 2.94-2.83 (m, 1H), 2.71-2.56 (m,2H), 2.55-2.42 (m, 2H), 1.96-1.84 (m, 2H), 1.18-1.15 (m, 1H), 1.00-0.92(m, 2H), 0.78-0.72 (m, 1H), 0.71-0.65 (m, 2H).

Example 17:(rac)-(2s,4s)-2-(1-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-3-(tert-butyl)benzene instead of 1-bromo-4-(tert-butyl)benzenein Step A. MS (ESI): mass calcd. for C₂₂H₂₈N₂O₃, 368.2; m/z found, 369.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.31-7.27 (m, 1H), 7.26-7.23 (m, 1H),7.21-7.18 (m, 1H), 7.04-6.95 (m, 1H), 5.93 (d, J=15.7 Hz, 1H), 4.36 (d,J=4.3 Hz, 2H), 4.25-3.89 (m, 1H), 3.88-3.58 (m, 3H), 2.96-2.83 (m, 1H),2.69-2.57 (m, 2H), 2.57-2.42 (m, 2H), 2.00-1.86 (m, 1H), 1.32 (d, J=2.3Hz, 9H), 1.20-1.14 (m, 1H), 0.80-0.72 (m, 1H).

Example 18:(rac)-(2s,4s)-2-(1-(4-Cyclopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-4-cyclopropylbenzene instead of 1-bromo-4-(tert-butyl)benzene inStep A. MS (ESI): mass calcd. for C₂₁H₂₄N₂O₃, 352.2; m/z found, 353.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.11-7.05 (m, 2H), 7.05-7.01 (m, 2H),5.89 (br s, 1H), 4.35 (d, J=4.5 Hz, 2H), 4.25-3.89 (m, 1H), 3.84-3.55(m, 3H), 2.95-2.82 (m, 1H), 2.67-2.56 (m, 2H), 2.55-2.42 (m, 2H),1.93-1.81 (m, 2H), 1.16-1.13 (m, 1H), 1.01-0.91 (m, 2H), 0.77-0.70 (m,1H), 0.70-0.62 (m, 2H).

Example 19:(rac)-(2s,4s)-2-(1-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-3-(trifluoromethoxy)benzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₁₉H₁₉F₃N₂O₄, 396.1; m/z found, 397.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.35 (td, J=8.0, 3.2 Hz, 1H), 7.15-7.07 (m, 2H), 7.00 (d, J=13.0 Hz,1H), 5.95 (d, J=7.4 Hz, 1H), 4.36 (d, J=1.6 Hz, 2H), 4.25-3.92 (m, 1H),3.89-3.56 (m, 3H), 2.96-2.82 (m, 1H), 2.69-2.57 (m, 2H), 2.57-2.43 (m,2H), 2.01-1.90 (m, 1H), 1.19 (t, J=7.1 Hz, 1H), 0.88-0.80 (m, 1H).

Example 20:(rac)-(2s,4s)-2-(1-(o-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-2-methylbenzene instead of 1-bromo-4-(tert-butyl)benzene in StepA. MS (ESI): mass calcd. for C₁₉H₂₂N₂O₃, 326.2; m/z found, 327.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 7.24 (s, 1H), 7.21-7.12 (m, 3H), 5.89 (d,J=11.2 Hz, 1H), 4.34 (d, J=17.2 Hz, 2H), 4.15-3.94 (m, 1H), 3.87-3.63(m, 2H), 3.50-3.31 (m, 1H), 2.96-2.77 (m, 1H), 2.71-2.42 (m, 4H), 2.39(d, J=2.4 Hz, 3H), 1.87-1.79 (m, 1H), 1.20-1.06 (m, 1H), 0.75 (q, J=4.8Hz, 1H).

Example 21:(rac)-(2s,4s)-2-(1-(m-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-3-methylbenzene instead of 1-bromo-4-(tert-butyl)benzene in StepA. MS (ESI): mass calcd. for C₁₉H₂₂N₂O₃, 326.2; m/z found, 327.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 7.21 (td, J=7.5, 3.0 Hz, 1H), 7.05 (t, J=7.0Hz, 1H), 7.01-6.95 (m, 2H), 5.95 (d, J=7.6 Hz, 1H), 4.36 (d, J=3.0 Hz,2H), 4.25-3.89 (m, 1H), 3.86-3.55 (m, 3H), 2.95-2.84 (m, 1H), 2.68-2.57(m, 2H), 2.57-2.43 (m, 2H), 2.34 (d, J=2.4 Hz, 3H), 1.99-1.86 (m, 1H),1.19-1.11 (m, 1H), 0.80-0.70 (m, 1H).

Example 22:(rac)-(2s,4s)-2-(1-(4-(Trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-4-(trifluoromethoxy)benzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₁₉H₁₉F₃N₂O₄, 396.1; m/z found, 397.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.24-7.14 (m, 4H), 6.09 (d, J=8.1 Hz, 1H), 4.36 (d, J=4.9 Hz, 2H),4.25-3.89 (m, 1H), 3.85-3.55 (m, 3H), 2.95-2.82 (m, 1H), 2.70-2.58 (m,2H), 2.57-2.43 (m, 2H), 2.00-1.84 (m, 1H), 1.19-1.15 (m, 1H), 0.84-0.78(m, 1H).

Example 23:(rac)-(2s,4s)-2-(1-(3-(Trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-3-(trifluoromethyl)benzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₁₉H₁₉F₃N₂O₃, 380.1; m/z found, 381.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.56-7.30 (m, 4H), 6.16 (d, J=5.4 Hz, 1H), 4.36 (d, J=1.9 Hz, 2H),4.25-3.93 (m, 1H), 3.90-3.57 (m, 3H), 2.97-2.84 (m, 1H), 2.72-2.60 (m,2H), 2.57-2.43 (m, 2H), 2.04-1.93 (m, 1H), 1.24-1.18 (m, 1H), 0.89-0.82(m, 1H).

Example 24:(rac)-(2s,4s)-2-(1-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-4-(trifluoromethyl)benzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₁₉H₁₉F₃N₂O₃, 380.1; m/z found, 381.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.57 (dd, J=8.2, 3.3 Hz, 2H), 7.32-7.26 (m, 2H), 6.21 (d, J=15.1 Hz,1H), 4.36 (d, J=2.7 Hz, 2H), 4.28-3.95 (m, 1H), 3.91-3.57 (m, 3H),2.98-2.83 (m, 1H), 2.74-2.57 (m, 2H), 2.55-2.41 (m, 2H), 2.08-1.94 (m,1H), 1.25-1.15 (m, 1H), 0.92-0.82 (m, 1H).

Example 25:(rac)-(2s,4s)-2-(1-(4-Methyl-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using5-bromo-2-methylbenzotrifluoride instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₀H₂₁F₃N₂O₃, 394.1; m/z found, 395.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.40 (d, J=16.8 Hz, 1H), 7.26-7.21 (m, 2H), 5.98 (d, J=8.8 Hz, 1H), 4.36(d, J=2.7 Hz, 2H), 4.25-3.92 (m, 1H), 3.89-3.54 (m, 3H), 2.93-2.84 (m,1H), 2.68-2.58 (m, 2H), 2.56-2.41 (m, 5H), 1.99-1.87 (m, 1H), 1.16 (dd,J=8.1, 5.3 Hz, 1H), 0.83-0.76 (m, 1H).

Example 26:(rac)-(2s,4s)-2-(1-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-4-(1-methylcyclopropyl)benzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₂H₂₆N₂O₃, 366.2; m/z found, 367.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.21 (dd, J=8.4, 2.1 Hz, 2H), 7.13-7.06 (m, 2H), 6.02 (d, J=7.9 Hz, 1H),4.35 (d, J=4.5 Hz, 2H), 4.25-3.89 (m, 1H), 3.85-3.54 (m, 3H), 2.94-2.81(m, 1H), 2.69-2.57 (m, 2H), 2.55-2.41 (m, 2H), 1.93-1.82 (m, 1H), 1.39(s, 3H), 1.18-1.13 (m, 1H), 0.83 (t, J=5.1 Hz, 2H), 0.78-0.70 (m, 3H).

Example 27:(rac)-(2r,4s)-2-(1-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-4-(1-methylcyclopropyl)benzene instead of1-bromo-4-(tert-butyl)benzene in Step A and using(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₃H₂₈N₂O₂, 364.2;m/z found, 365.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.23-7.17 (m, 2H),7.13-7.07 (m, 2H), 6.13 (s, 1H), 4.25-3.89 (m, 1H), 3.85-3.52 (m, 3H),2.95-2.83 (m, 1H), 2.58-2.45 (m, 2H), 2.45-2.31 (m, 4H), 2.26-2.15 (m,2H), 1.92-1.81 (m, 1H), 1.39 (d, J=1.6 Hz, 3H), 1.18-1.07 (m, 1H), 0.83(t, J=5.1 Hz, 2H), 0.78-0.67 (m, 3H).

Example 28:(rac)-(2s,4s)-2-(1-(4-Phenoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using4-bromodiphenyl ether instead of 1-bromo-4-(tert-butyl)benzene in StepA. MS (ESI): mass calcd. for C₂₄H₂₄N₂O₄, 404.2; m/z found, 405.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 7.36-7.30 (m, 2H), 7.19-7.07 (m, 3H),7.02-6.93 (m, 4H), 5.99 (s, 1H), 4.35 (d, J=5.1 Hz, 2H), 4.25-3.89 (m,1H), 3.86-3.56 (m, 3H), 2.92-2.83 (m, 1H), 2.69-2.58 (m, 2H), 2.56-2.41(m, 2H), 1.93-1.83 (m, 1H), 1.19-1.14 (m, 1H), 0.79-0.71 (m, 1H).

Example 29:(rac)-(2s,4s)-2-(1-(3-Phenoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using3-bromodiphenyl ether instead of 1-bromo-4-(tert-butyl)benzene in StepA. MS (ESI): mass calcd. for C₂₄H₂₄N₂O₄, 404.2; m/z found, 405.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 7.38-7.31 (m, 2H), 7.30-7.24 (m, 1H),7.15-7.08 (m, 1H), 6.99 (d, J=8.5 Hz, 2H), 6.91 (dd, J=11.4, 7.9 Hz,1H), 6.87-6.81 (m, 2H), 5.96 (d, J=17.2 Hz, 1H), 4.35 (d, J=1.0 Hz, 2H),4.25-3.89 (m, 1H), 3.88-3.54 (m, 3H), 2.94-2.80 (m, 1H), 2.69-2.57 (m,2H), 2.55-2.41 (m, 2H), 1.98-1.82 (m, 1H), 1.19-1.14 (m, 1H), 0.78 (dd,J=10.8, 5.1 Hz, 1H).

Example 30:(rac)-(2s,4s)-2-(1-(3-Chloro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using4-bromo-2-chlorotoluene instead of 1-bromo-4-(tert-butyl)benzene in StepA. MS (ESI): mass calcd. for C₁₉H₂₁ClN₂O₃, 360.1; m/z found, 361.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.12 (m, 2H), 7.04-6.92 (m, 1H),5.85 (s, 1H), 4.35 (d, J=1.5 Hz, 2H), 4.25-3.89 (m, 1H), 3.82-3.54 (m,3H), 2.95-2.80 (m, 1H), 2.68-2.56 (m, 2H), 2.55-2.44 (m, 2H), 2.34 (d,J=2.2 Hz, 3H), 1.95-1.85 (m, 1H), 1.17-1.13 (m, 1H), 0.81-0.70 (m, 1H).

Example 31:(rac)-(2s,4s)-2-(1-(3-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-3-(1-methylcyclopropyl)benzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₂H₂₆N₂O₃, 366.2; m/z found, 367.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.25-7.20 (m, 1H), 7.16-7.10 (m, 1H), 7.09-7.06 (m, 1H), 7.02-6.93 (m,1H), 6.07 (d, J 27.9 Hz, 1H), 4.36 (d, J=3.0 Hz, 2H), 4.25-3.89 (m, 1H),3.88-3.56 (m, 3H), 2.98-2.80 (m, 1H), 2.69-2.59 (m, 2H), 2.56-2.42 (m,2H), 1.97-1.86 (m, 1H), 1.39 (d, J=2.8 Hz, 3H), 1.19-1.13 (m, 1H),0.87-0.82 (m, 2H), 0.80-0.71 (m, 3H).

Example 32:(rac)-(2s,4s)-2-(1-(4-Cyclopropyl-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-4-cyclopropyl-2-methylbenzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₂H₂₆N₂O₃, 366.2; m/z found, 367.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.20-7.09 (m, 1H), 6.94-6.78 (m, 2H), 6.17 (d, J=40.5 Hz, 1H), 4.42-4.29(m, 2H), 4.13-3.92 (m, 1H), 3.87-3.58 (m, 2H), 3.47-3.28 (m, 1H),2.92-2.75 (m, 1H), 2.69-2.57 (m, 2H), 2.55-2.36 (m, 2H), 2.34 (d, J=2.8Hz, 3H), 1.90-1.73 (m, 2H), 1.08 (ddd, J=17.8, 7.8, 5.1 Hz, 1H),0.99-0.88 (m, 2H), 0.74-0.59 (m, 3H).

Example 33:(rac)-(2s,4s)-2-(1-(2-Methyl-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-2-methyl-4-(trifluoromethyl)benzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₀H₂₁F₃N₂O₃, 394.1; m/z found, 395.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.46-7.32 (m, 3H), 6.06 (d, J=22.0 Hz, 1H), 4.39-4.26 (m, 2H), 4.18-3.97(m, 1H), 3.86-3.61 (m, 2H), 3.49-3.30 (m, 1H), 2.94-2.76 (m, 1H),2.69-2.57 (m, 2H), 2.55-2.38 (m, 5H), 1.91-1.82 (m, 1H), 1.19-1.07 (m,1H), 0.85-0.79 (m, 1H).

Example 34:(rac)-(2s,4s)-2-(1-(2-Methyl-4-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-2-methyl-4-(trifluoromethoxy)benzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₀H₂₁F₃N₂O₄, 410.1; m/z found, 411.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.27 (dd, J=11.6, 8.3 Hz, 1H), 7.04-6.95 (m, 2H), 5.96 (d, J=15.4 Hz,1H), 4.34 (d, J=16.7 Hz, 2H), 4.16-3.95 (m, 1H), 3.86-3.60 (m, 2H),3.48-3.29 (m, 1H), 2.97-2.75 (m, 1H), 2.69-2.41 (m, 4H), 2.40 (d, J=1.9Hz, 3H), 1.87-1.78 (m, 1H), 1.17-1.05 (m, 1H), 0.81-0.75 (m, 1H).

Example 35:(rac)-(2s,4s)-2-(1-(3-Methyl-4-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-3-methyl-4-(trifluoromethoxy)benzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₀H₂₁F₃N₂O₄, 410.1; m/z found, 411.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.18-7.09 (m, 1H), 7.06 (s, 1H), 7.01 (td, J=8.6, 1.9 Hz, 1H), 6.25 (d,J=5.1 Hz, 1H), 4.36 (d, J=4.4 Hz, 2H), 4.25-3.89 (m, 1H), 3.85-3.57 (m,3H), 2.96-2.81 (m, 1H), 2.71-2.60 (m, 2H), 2.55-2.41 (m, 2H), 2.30 (d,J=2.6 Hz, 3H), 1.97-1.86 (m, 1H), 1.17-1.11 (m, 1H), 0.81-0.74 (m, 1H).

Example 36:(rac)-(2s,4s)-2-(1-(3-Methyl-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-3-methyl-4-(trifluoromethyl)benzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₀H₂₁F₃N₂O₃, 394.1; m/z found, 395.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.54 (dd, J=8.5, 3.0 Hz, 1H), 7.08-7.01 (m, 2H), 5.98 (s, 1H), 4.36 (d,J=1.7 Hz, 2H), 4.25-3.95 (m, 1H), 3.91-3.56 (m, 3H), 2.95-2.84 (m, 1H),2.68-2.57 (m, 2H), 2.57-2.48 (m, 2H), 2.47 (s, 3H), 2.04-1.92 (m, 1H),1.18 (t, J=6.7 Hz, 1H), 0.87-0.79 (m, 1H).

Example 37:(rac)-(2s,4s)-2-(1-(3-Fluoro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-3-fluoro-4-methylbenzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₁₉H₂₁FN₂O₃, 344.2; m/z found, 345.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.11 (td, J=8.0, 2.5 Hz, 1H), 6.89-6.77 (m, 2H), 6.09 (d, J=9.1 Hz, 1H),4.36 (d, J=1.9 Hz, 2H), 4.25-3.89 (m, 1H), 3.84-3.53 (m, 3H), 2.95-2.80(m, 1H), 2.69-2.57 (m, 2H), 2.55-2.41 (m, 2H), 2.26-2.22 (m, 3H),1.94-1.84 (m, 1H), 1.17-1.08 (m, 1H), 0.82-0.70 (m, 1H).

Example 38:(2s,4S)-2-((1R,5S,6S)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: 2-(Diiodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. In anoven-dried pressure vial under N₂, pinacol(dichloromethyl)boronate (0.4mL, 2.08 mmol) was taken up in acetone (4.4 mL). To this was added NaI(721 mg, 4.78 mmol) and the reaction was heated to 55° C. for 72 h. Thereaction was cooled to rt, filtered through Celite® with acetone, andconcentrated under reduced pressure. The residue was taken up in DCM andexcess iodine was quenched with sodium thiosulfate and magnesium sulfateby shaking the flask until the orange color disappeared. The slurry wasfiltered through Celite® with DCM, concentrated under reduced pressure,and used without further purification in subsequent steps. Compound doesnot ionize with ESI LCMS.

Step B: tert-butyl(1R,5S,6s)-6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate.In an oven-dried flask under N₂, chromium(II) chloride (1.0 g, 8.14mmol) was taken up in THF (13.5 mL). TMEDA (1.22 mL, 8.14 mmol) wasadded and this was stirred at rt for 25 min.2-(Diiodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (801 mg, 2.03mmol) was added and this was stirred at rt for 30 min. Finally,tert-butyl 2,5 dihydro-1H-pyrrole-1-carboxylate (237 mg, 1.36 mmol) wasadded and this was stirred at 50° C. for 20 h. The reaction was quenchedwith water and extracted with EtOAc. The combined organic layers werewashed with brine, dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The crude material was purified by FCC on silica(0-15-50% EtOAc in hexane) to afford the title compound (62 mg, 15%yield). MS (ESI): mass calcd. for C₁₆H₂₈BNO₄, 309.2; m/z found, 254.2[M+2H-tBu]⁺.

Step C: tert-Butyl(1R,5S,6s)-6-(3-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate.In an oven-dried pressure vial under N₂ was combinedbis(dibenzylideneacetone)palladium (Pd(dba)₂) (1.9 mg, 0.003 mmol),2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos) (2.7 mg, 0.006mmol), potassium tert-butoxide (KOtBu) (29 mg, 0.259 mmol),1-iodo-3-(trifluoromethoxy)benzene (31 μL, 0.194 mmol), tert-butanol(0.26 mL), and 1,2-dimethoxyethane (DME) (0.78 mL). To this was addedtert-butyl(1R,5S,6s)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(20 mg, 0.065 mmol) and this was heated to 80° C. for 20 h. The reactionwas quenched with water and extracted with EtOAc. The combined organiclayers were dried over sodium sulfate, filtered, and concentrated underreduced pressure. Purification via reverse phase HPLC (5-95% ACN in 20mM NH₄OH in water) afforded the title compound (6 mg, 27% yield). MS(ESI): mass calcd. for C₁₇H₂₀F₃NO₃, 343.1; m/z found, 288.1 [M+2H-tBu]⁺.

Step D:(1R,5S,6s)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexanehydrochloride. To tert-butyl(1R,5S,6s)-6-(3-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(6 mg, 0.017 mmol) in MeOH (0.1 mL) was added HCl in 1,4-dioxane (4 M,0.1 mL). This was heated to 45° C. for 1 hour before concentrating underreduced pressure. The title compound was used without furtherpurification in the next step. MS (ESI): mass calcd. for C₁₂H₁₃ClF₃NO279.1; m/z found, 244.1 [M−Cl]⁺.

Step E:(2s,4S)-2-((1R,5S,6S)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.(1R,5S,6s)-6-(3-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexanehydrochloride was taken up in DMF (0.2 mL) and to this was added(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 3.1 mg, 0.018 mmol), DIPEA (9.2 μL, 0.052 mmol), andHATU (7.5 mg, 0.019 mmol). The reaction mixture was stirred at roomtemperature for 2 hours. The reaction mixture was filtered through aPTFE filter with MeOH and purified via reverse phase HPLC (5-95% ACN in20 mM NH₄OH in water) to afford the title compound (6 mg, 87% yield). MS(ESI): mass calcd. for C₁₉H₁₉F₃N₂O₄, 396.1; m/z found, 397.3 [M+H]⁺. ¹HNMR (400 MHz, Chloroform-d) δ 7.29 (d, J=8.0 Hz, 1H), 7.06-7.01 (m, 1H),6.95 (dt, J=7.7, 1.3 Hz, 1H), 6.85 (dt, J=2.5, 1.2 Hz, 1H), 6.22 (s,1H), 4.36 (s, 2H), 4.00 (d, J=12.3 Hz, 1H), 3.72-3.63 (m, 2H), 3.57 (dd,J=12.3, 3.4 Hz, 1H), 2.88 (tt, J=8.5, 7.0 Hz, 1H), 2.71-2.59 (m, 2H),2.54-2.44 (m, 2H), 1.97-1.86 (m, 2H), 1.67 (d, J=3.5 Hz, 1H).

Example 39:(rac)-(2s,4s)-2-(6-Phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 1 using6-phenyl-3-azabicyclo[4.1.0]heptane hydrochloride instead of1-(p-tolyl)-3-azabicyclo[3.1.0]hexane. MS (ESI): mass calcd. forC₁₉H₂₂N₂O₃, 326.2; m/z found, 327.1 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 7.34-7.16 (m, 5H), 6.28 (d, J=12.9 Hz, 1H), 4.38 (d,J=8.8 Hz, 2H), 4.03-3.63 (m, 2H), 3.56-3.42 (m, 1H), 3.41-3.18 (m, 1H),2.98 (dp, J=18.7, 8.1 Hz, 1H), 2.75-2.62 (m, 2H), 2.55-2.40 (m, 2H),2.24-2.03 (m, 2H), 1.56-1.37 (m, 1H), 1.09-1.01 (m, 1H), 0.79 (q, J=5.0Hz, 1H).

Example 40:(2s,4S)-2-((1R,6S)-6-Phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 39 (Stationary phase: Chiralpak AD, 5 μm250×21 mm, Mobile phase: 40% MeOH:isopropanol (1:1) with 0.2%isopropylamine, 60% CO₂). MS (ESI): mass calcd. for C₁₉H₂₂N₂O₃, 326.2;m/z found, 327.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) δ 7.34-7.16 (m,5H), 6.42 (d, J=14.0 Hz, 1H), 4.38 (d, J=10.8 Hz, 2H), 4.03-3.58 (m,2H), 3.50 (dp, J=19.0, 6.9 Hz, 1H), 3.41-3.18 (m, 1H), 2.98 (dp, J=24.2,8.2 Hz, 1H), 2.70 (qd, J=10.4, 5.3 Hz, 2H), 2.47 (td, J=12.5, 8.2 Hz,2H), 2.22-2.02 (m, 2H), 1.56-1.37 (m, 1H), 1.05 (dt, J=9.1, 4.8 Hz, 1H),0.79 (q, J=5.4 Hz, 1H).

Example 41:(2s,4R)-2-((1S,6R)-6-Phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 39 (Stationary phase: Chiralpak AD, 5 μm250×21 mm, Mobile phase: 40% MeOH:isopropanol (1:1) with 0.2%isopropylamine, 60% CO₂). MS (ESI): mass calcd. for C₁₉H₂₂N₂O₃, 326.2;m/z found, 327.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) δ 7.29 (t, J=7.6Hz, 2H), 7.25-7.16 (m, 3H), 6.55 (d, J=11.8 Hz, 1H), 4.38 (d, J=10.7 Hz,2H), 4.03-3.60 (m, 2H), 3.50 (dp, J=19.0, 6.9 Hz, 1H), 3.41-3.18 (m,1H), 2.97 (dp, J=24.4, 8.2 Hz, 1H), 2.70 (qd, J=10.4, 5.3 Hz, 2H), 2.47(td, J=12.5, 8.2 Hz, 2H), 2.22-2.02 (m, 2H), 1.53-1.38 (m, 1H),1.09-1.01 (m, 1H), 0.78 (q, J=5.4 Hz, 1H).

Example 42:(rac)-(2s,4s)-2-(7,7-Difluoro-6-phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 1 using7,7-difluoro-6-phenyl-3-azabicyclo[4.1.0]heptane hydrochloride insteadof 1-(p-tolyl)-3-azabicyclo[3.1.0]hexane. MS (ESI): mass calcd. forC₁₉H₂₀F₂N₂O₃, 362.1; m/z found, 363.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ7.42-7.24 (m, 5H), 4.51 (d, J=0.7 Hz, 1H), 4.48-4.42 (m, 1H), 4.05-3.76(m, 2H), 3.73-3.50 (m, 1H), 3.30-3.01 (m, 2H), 2.64-2.37 (m, 4H),2.34-2.12 (m, 2H), 2.01-1.85 (m, 1H).

Example 43:(rac)-(2s,4s)-2-(6-(m-Tolyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 3-bromotoluene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₀H₂₄N₂O₃, 340.2; m/z found, 341.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.19 (t, J=7.6 Hz, 1H), 7.07-6.99 (m, 3H), 5.75 (d, J=20.8 Hz, 1H), 4.37(d, J=8.8 Hz, 2H), 4.02-3.86 (m, 1H), 3.74 (ddd, J=15.3, 13.1, 3.3 Hz,1H), 3.56-3.41 (m, 1H), 3.39-3.17 (m, 1H), 3.07-2.92 (m, 1H), 2.71-2.59(m, 2H), 2.54-2.44 (m, 2H), 2.33 (s, 3H), 2.22-2.01 (m, 2H), 1.52-1.37(m, 1H), 1.08-1.02 (m, 1H), 0.79-0.72 (m, 1H).

Example 44:(2s,4*R)-2-((1*S,6*R)-6-(m-Tolyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 43 (Stationary phase: Chiralpak AD, 5 μm250×21 mm, Mobile phase: 40% MeOH with 0.2% TEA, 60% CO₂). MS (ESI):mass calcd. for C₂₀H₂₄N₂O₃, 340.2; m/z found, 341.1 [M+H]⁺. ¹H NMR (400MHz, Chloroform-d) δ 7.18 (t, J=7.5 Hz, 1H), 7.07-6.98 (m, 3H), 6.20 (d,J=13.5 Hz, 1H), 4.38 (d, J=8.6 Hz, 2H), 4.02-3.40 (m, 3H), 3.40-3.17 (m,1H), 3.12-2.89 (m, 1H), 2.74-2.61 (m, 2H), 2.54-2.41 (m, 2H), 2.33 (s,3H), 2.21-2.06 (m, 2H), 1.52-1.36 (m, 1H), 1.04 (dt, J=9.0, 4.7 Hz, 1H),0.76 (td, J=5.3, 2.9 Hz, 1H).

Example 45:(2s,4*5)-2-((1*R,6*S)-6-(m-Tolyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 43 (Stationary phase: Chiralpak AD, 5 μm250×21 mm, Mobile phase: 40% MeOH with 0.2% TEA, 60% CO₂). MS (ESI):mass calcd. for C₂₀H₂₄N₂O₃, 340.2; m/z found, 341.2 [M+H]⁺. ¹H NMR (400MHz, Chloroform-d) δ 7.18 (dd, J=8.0, 7.1 Hz, 1H), 7.06-6.97 (m, 3H),6.25-6.11 (m, 1H), 4.38 (d, J=8.6 Hz, 2H), 4.02-3.39 (m, 3H), 3.39-3.18(m, 1H), 3.05-2.89 (m, 1H), 2.72-2.61 (m, 2H), 2.53-2.41 (m, 2H), 2.33(s, 3H), 2.22-2.05 (m, 2H), 1.52-1.34 (m, 1H), 1.04 (dt, J=9.1, 4.7 Hz,1H), 0.76 (td, J=5.3, 2.9 Hz, 1H).

Example 46:(rac)-(2s,4s)-2-(6-(3-Fluoro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-3-fluoro-4-methylbenzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₀H₂₃FN₂O₃, 358.2; m/z found, 359.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.09 (t, J=8.0 Hz, 1H), 6.92-6.77 (m, 2H), 6.00 (d, J=18.1 Hz, 1H), 4.37(d, J=7.9 Hz, 2H), 3.99-3.86 (m, 1H), 3.73 (ddd, J=15.3, 13.2, 3.3 Hz,1H), 3.56-3.41 (m, 1H), 3.39-3.18 (m, 1H), 3.06-2.90 (m, 1H), 2.72-2.59(m, 2H), 2.53-2.41 (m, 2H), 2.23 (d, J=1.6 Hz, 3H), 2.18-2.01 (m, 2H),1.51-1.33 (m, 1H), 1.06-0.97 (m, 1H), 0.81-0.71 (m, 1H).

Example 47:(2s,4*R)-2-((1*S,6*R)-6-(3-Fluoro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 46 (Stationary phase: Chiralcel OD-H 5 μm250×20 mm, Mobile phase: 15% MeOH:isopropanol (1:1) with 0.2%isopropylamine, 85% CO₂). MS (ESI): mass calcd. for C₂₀H₂₃FN₂O₃, 358.2;m/z found, 359.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.08 (td,J=8.0, 0.9 Hz, 1H), 6.91-6.82 (m, 2H), 6.37 (d, J=13.7 Hz, 1H), 4.37 (d,J=7.8 Hz, 2H), 3.98-3.61 (m, 2H), 3.55-3.39 (m, 1H), 3.39-3.17 (m, 1H),3.03-2.89 (m, 1H), 2.73-2.61 (m, 2H), 2.53-2.41 (m, 2H), 2.22 (d, J=1.8Hz, 3H), 2.19-2.00 (m, 2H), 1.51-1.33 (m, 1H), 1.02 (dt, J=9.1, 5.2 Hz,1H), 0.78 (q, J=5.2 Hz, 1H).

Example 48:(2s,4*5)-2-((1*R,6*5)-6-(3-Fluoro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 46 (Stationary phase: Chiralcel OD-H 5 μm250×20 mm, Mobile phase: 15% MeOH:isopropanol (1:1) with 0.2%isopropylamine, 85% CO₂). MS (ESI): mass calcd. for C₂₀H₂₃FN₂O₃, 358.2;m/z found, 359.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.09 (td,J=8.1, 0.9 Hz, 1H), 6.91-6.82 (m, 2H), 6.27 (d, J=14.9 Hz, 1H), 4.37 (d,J=7.8 Hz, 2H), 3.98-3.61 (m, 2H), 3.56-3.40 (m, 1H), 3.39-3.17 (m, 1H),3.05-2.89 (m, 1H), 2.72-2.62 (m, 2H), 2.52-2.41 (m, 2H), 2.23 (d, J=1.8Hz, 3H), 2.20-2.00 (m, 2H), 1.51-1.33 (m, 1H), 1.02 (dt, J=9.0, 5.4 Hz,1H), 0.78 (q, J=5.2 Hz, 1H).

Example 49:(rac)-(2s,4s)-2-(6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-3-(trifluoromethoxy)benzene insteadof 1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₀H₂₁F₃N₂O₄, 410.1; m/z found, 411.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.31 (t, J=8.2 Hz, 1H), 7.15 (dd, J=6.5, 1.3 Hz, 1H), 7.05 (d, J=7.6 Hz,2H), 6.25 (d, J=14.0 Hz, 1H), 4.38 (d, J=8.0 Hz, 2H), 3.98-3.92 (m, 1H),3.76 (ddd, J=15.3, 13.2, 3.3 Hz, 1H), 3.58-3.43 (m, 1H), 3.41-3.21 (m,1H), 3.07-2.90 (m, 1H), 2.74-2.63 (m, 2H), 2.55-2.43 (m, 2H), 2.24-2.05(m, 2H), 1.57-1.38 (m, 1H), 1.11-1.02 (m, 1H), 0.87-0.80 (m, 1H).

Example 50:(2s,4*R)-2-((1*S,6*R)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 49 (Stationary phase: Chiralpak AD, 5 μm250×30 mm, Mobile phase: 25% MeOH with 0.2% TEA, 75% CO₂). MS (ESI):mass calcd. for C₂₀H₂₁F₃N₂O₄, 410.1; m/z found, 411.1 [M+H]⁺. ¹H NMR(500 MHz, Chloroform-d) δ 7.35-7.28 (m, 1H), 7.17-7.13 (m, 1H),7.08-7.03 (m, 2H), 5.90 (d, J=23.3 Hz, 1H), 4.38 (d, J=10.1 Hz, 2H),4.00-3.90 (m, 1H), 3.85-3.65 (m, 1H), 3.56-3.44 (m, 1H), 3.39-3.22 (m,1H), 3.05-2.91 (m, 1H), 2.70-2.59 (m, 2H), 2.54-2.44 (m, 2H), 2.21-2.05(m, 2H), 1.55-1.40 (m, 1H), 1.07 (td, J=8.7, 5.4 Hz, 1H), 0.84 (q, J=5.5Hz, 1H).

Example 51:(2s,4*S)-2-((1*R,6*S)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 49 (Stationary phase: Chiralpak AD, 5 μm250×30 mm, Mobile phase: 25% MeOH with 0.2% TEA, 75% CO₂). MS (ESI):mass calcd. for C₂₀H₂₁F₃N₂O₄, 410.1; m/z found, 411.1 [M+H]⁺. ¹H NMR(500 MHz, Chloroform-d) δ 7.34-7.28 (m, 1H), 7.18-7.12 (m, 1H),7.08-7.03 (m, 2H), 6.09 (d, J=19.8 Hz, 1H), 4.38 (d, J=10.0 Hz, 2H),3.99-3.90 (m, 1H), 3.86-3.64 (m, 1H), 3.56-3.44 (m, 1H), 3.39-3.21 (m,1H), 3.05-2.91 (m, 1H), 2.72-2.60 (m, 2H), 2.54-2.44 (m, 2H), 2.21-2.04(m, 2H), 1.55-1.40 (m, 1H), 1.07 (td, J=8.7, 5.4 Hz, 1H), 0.84 (q, J=5.6Hz, 1H).

Example 52:(rac)-(2r,4s)-2-(6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-3-(trifluoromethoxy)benzene insteadof 1-bromo-4-(tert-butyl)benzene in Step A and using(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₁H₂₃F₃N₂O₃,408.2; m/z found, 409.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (s,1H), 7.43 (t, J=7.9 Hz, 1H), 7.29 (d, J=7.3 Hz, 1H), 7.21-7.14 (m, 2H),3.91-3.56 (m, 2H), 3.43-3.35 (m, 1H), 3.29-3.22 (m, 1H), 3.09-2.98 (m,1H), 2.36-2.17 (m, 4H), 2.17-2.11 (m, 4H), 2.11-1.99 (m, 2H), 1.54-1.44(m, 1H), 1.05-0.97 (m, 1H), 0.84 (t, J=5.3 Hz, 1H).

Example 53:(rac)-(2s,4s)-2-(6-(o-Tolyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 2-bromotoluene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₀H₂₄N₂O₃, 340.2; m/z found, 341.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.21-7.10 (m, 4H), 5.78 (d, J=23.5 Hz, 1H), 4.38 (d, J=13.0 Hz, 2H),4.05-3.92 (m, 1H), 3.90-3.63 (m, 2H), 3.34-3.22 (m, 1H), 3.10-2.91 (m,1H), 2.71-2.61 (m, 2H), 2.56-2.44 (m, 2H), 2.38 (s, 3H), 2.11-1.87 (m,2H), 1.48-1.34 (m, 1H), 1.04-0.94 (m, 1H), 0.74 (dd, J=9.1, 5.1 Hz, 1H).

Example 54:(rac)-(2s,4s)-2-(6-(4-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-4-(trifluoromethoxy)benzene insteadof 1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₀H₂₁F₃N₂O₄, 410.1; m/z found, 411.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.26-7.22 (m, 2H), 7.14 (d, J=8.2 Hz, 2H), 6.00 (d, J=15.6 Hz, 1H), 4.38(d, J=8.5 Hz, 2H), 4.03-3.65 (m, 2H), 3.59-3.41 (m, 1H), 3.40-3.18 (m,1H), 3.08-2.92 (m, 1H), 2.73-2.61 (m, 2H), 2.57-2.43 (m, 2H), 2.20-2.02(m, 2H), 1.55-1.38 (m, 1H), 1.09-1.00 (m, 1H), 0.86-0.77 (m, 1H).

Example 55:(rac)-(2r,4s)-2-(6-(4-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-4-(trifluoromethoxy)benzene insteadof 1-bromo-4-(tert-butyl)benzene in Step A and using(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₁H₂₃F₃N₂O₃,408.2; m/z found, 409.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (s,1H), 7.37 (d, J=8.6 Hz, 2H), 7.27 (d, J=8.2 Hz, 2H), 3.90-3.54 (m, 2H),3.43-3.35 (m, 1H), 3.28-3.23 (m, 1H), 3.10-2.95 (m, 1H), 2.40-2.24 (m,3H), 2.24-2.17 (m, 2H), 2.13 (s, 4H), 1.50-1.37 (m, 1H), 1.06-0.94 (m,1H), 0.94-0.73 (m, Hz, 2H).

Example 56:(rac)-(2s,4s)-2-(6-(p-Tolyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 4-bromotoluene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₀H₂₄N₂O₃, 340.2; m/z found, 341.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.16-7.08 (m, 4H), 5.88 (d, J=19.8 Hz, 1H), 4.37 (d, J=8.9 Hz, 2H),4.03-3.62 (m, 2H), 3.48 (td, J=6.7, 2.5 Hz, 1H), 3.40-3.18 (m, 1H),3.09-2.92 (m, 1H), 2.71-2.60 (m, 2H), 2.55-2.42 (m, 2H), 2.32 (s, 3H),2.21-2.00 (m, 2H), 1.51-1.34 (m, 1H), 1.06-0.99 (m, 1H), 0.79-0.72 (m,1H).

Example 57:(rac)-(2s,4s)-2-(6-(3-(Trifluoromethyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-3-(trifluoromethyl)benzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₀H₂₁F₃N₂O₃, 394.1; m/z found, 395.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.47 (dd, J=5.6, 3.1 Hz, 2H), 7.42 (dd, J=6.1, 1.5 Hz, 2H), 5.88 (d,J=18.2 Hz, 1H), 4.38 (d, J=8.7 Hz, 2H), 3.96 (d, J=3.5 Hz, 1H), 3.77(ddd, J=15.2, 13.2, 3.2 Hz, 1H), 3.60-3.43 (m, 1H), 3.41-3.21 (m, 1H),3.11-2.91 (m, 1H), 2.75-2.59 (m, 2H), 2.57-2.45 (m, 2H), 2.18-2.10 (m,2H), 1.59-1.41 (m, 1H), 1.14-1.03 (m, 1H), 0.92-0.77 (m, 1H).

Example 58:(rac)-(2s,4s)-2-(6-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-4-(trifluoromethyl)benzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₀HnF₃N₂O₃, 394.1; m/z found, 395.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.55 (d, J=8.2 Hz, 2H), 7.33 (d, J=7.5 Hz, 2H), 6.35 (d, J=11.1 Hz, 1H),4.38 (d, J=8.0 Hz, 2H), 3.99-3.90 (m, 1H), 3.89-3.65 (m, 1H), 3.60-3.43(m, 1H), 3.43-3.21 (m, 1H), 3.07-2.88 (m, 1H), 2.74-2.63 (m, 2H),2.54-2.42 (m, 2H), 2.24-2.06 (m, 2H), 1.59-1.41 (m, 1H), 1.12-1.03 (m,1H), 0.86 (dd, J=9.3, 5.3 Hz, 1H).

Example 59:(rac)-(2r,4s)-2-(6-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-4-(trifluoromethyl)benzene instead of1-bromo-4-(tert-butyl)benzene in Step A and using(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₁H₂₃F₃N₂O₂,392.2; m/z found, 393.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (s,1H), 7.64 (d, J=8.3 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 3.90-3.59 (m, 2H),3.44-3.35 (m, 1H), 3.29-3.25 (m, 1H), 3.11-2.97 (m, 1H), 2.35-2.26 (m,2H), 2.24-2.01 (m, 8H), 1.57-1.45 (m, 1H), 1.10-0.99 (m, 1H), 0.88 (t,J=5.4 Hz, 1H).

Example 60:(rac)-(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-3-(tert-butyl)benzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₃H₃₀N₂O₃, 382.2; m/z found, 383.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.25-7.22 (m, 3H), 7.08-7.01 (m, 1H), 6.04 (d, J=16.3 Hz, 1H), 4.38 (d,J=9.0 Hz, 2H), 4.03-3.63 (m, 2H), 3.50 (t, J=6.4 Hz, 1H), 3.41-3.19 (m,1H), 3.08-2.92 (m, 1H), 2.73-2.61 (m, 2H), 2.55-2.41 (m, 2H), 2.26-2.05(m, 2H), 1.55-1.38 (m, 1H), 1.31 (s, 9H), 1.09-0.99 (m, 1H), 0.82-0.73(m, 1H).

Example 61:(rac)-(2r,4s)-2-(6-(3-(tert-Butyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-3-(tert-butyl)benzene instead of1-bromo-4-(tert-butyl)benzene in Step A and using(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₄H₃₂N₂O₂, 380.2;m/z found, 381.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (s, 1H),7.25-7.16 (m, 3H), 7.08-7.01 (m, 1H), 3.92-3.55 (m, 2H), 3.32-3.17 (m,2H), 3.10-2.95 (m, 1H), 2.36-2.16 (m, 4H), 2.15-2.12 (m, 4H), 2.08-1.94(m, 2H), 1.47-1.36 (m, 1H), 1.26 (s, J=11.3 Hz, 9H), 0.98-0.90 (m, 1H),0.78 (q, J=5.1 Hz, 1H).

Example 62:(rac)-(2s,4s)-2-(6-(4-(tert-Butyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) in Step A. MS (ESI): mass calcd. for C₂₃H₃₀N₂O₃, 382.2;m/z found, 383.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.29 (m, 2H),7.15 (dd, J=8.3, 1.2 Hz, 2H), 6.03 (d, J=16.0 Hz, 1H), 4.37 (d, J=8.2Hz, 2H), 4.03-3.61 (m, 2H), 3.48 (t, J=6.4 Hz, 1H), 3.39-3.17 (m, 1H),3.06-2.88 (m, 1H), 2.71-2.60 (m, 2H), 2.53-2.40 (m, 2H), 2.25-2.06 (m,2H), 1.53-1.36 (m, 1H), 1.30 (s, 9H), 1.08-1.02 (m, 1H), 0.77 (dd,J=11.4, 5.5 Hz, 1H).

Example 63:(rac)-(2r,4s)-2-(6-(4-(tert-Butyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) in Step A and using(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₄H₃₂N₂O₂, 380.2;m/z found, 381.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (s, 1H), 7.29(d, J=8.3 Hz, 2H), 7.15 (d, J=8.3 Hz, 2H), 3.90-3.55 (m, 2H), 3.42-3.37(m, 1H), 3.29-3.17 (m, 1H), 3.11-2.94 (m, 1H), 2.37-2.18 (m, 4H), 2.13(d, J=6.1 Hz, 4H), 2.08-1.92 (m, 2H), 1.44-1.31 (m, 1H), 1.25 (s, 9H),0.98-0.88 (m, 1H), 0.76 (t, J=4.8 Hz, 1H).

Example 64:(rac)-(2s,4s)-2-(6-(3-Cyclopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-3-cyclopropylbenzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₂H₂₆N₂O₃, 366.2; m/z found, 367.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.18 (t, J=7.6 Hz, 1H), 7.04-6.98 (m, 1H), 6.97 (br s, 1H), 6.87 (d,J=7.6 Hz, 1H), 5.94 (d, J=18.3 Hz, 1H), 4.37 (d, J=8.8 Hz, 2H),4.03-3.61 (m, 2H), 3.59-3.41 (m, 1H), 3.39-3.17 (m, 1H), 3.09-2.89 (m,1H), 2.73-2.56 (m, 2H), 2.55-2.40 (m, 2H), 2.23-2.01 (m, 2H), 1.93-1.79(m, 1H), 1.53-1.37 (m, 1H), 1.08-1.00 (m, 1H), 1.00-0.90 (m, 2H),0.79-0.71 (m, 1H), 0.70-0.60 (m, 2H).

Example 65:(rac)-(2r,4s)-2-(6-(3-Cyclopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-3-cyclopropylbenzene instead of1-bromo-4-(tert-butyl)benzene in Step A and using(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₃H₂₈N₂O₂, 364.2;m/z found, 365.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (s, 1H), 7.15(t, J=7.6 Hz, 1H), 7.03-6.93 (m, 2H), 6.83 (d, J=7.7 Hz, 1H), 3.89-3.56(m, 2H), 3.41-3.36 (m, 1H), 3.30-3.19 (m, 1H), 3.10-2.95 (m, 1H),2.35-2.16 (m, 4H), 2.16-2.11 (m, 4H), 2.06-1.95 (m, 2H), 1.88 (tt,J=8.4, 5.1 Hz, 1H), 1.43-1.36 (m, 1H), 0.98-0.87 (m, 3H), 0.75 (t, J=5.2Hz, 1H), 0.66-0.61 (m, 2H).

Example 66:(rac)-(2s,4s)-2-(6-(4-Cyclopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-4-cyclopropylbenzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₂H₂₆N₂O₃, 366.2; m/z found, 367.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.14-7.08 (m, 2H), 7.03-6.98 (m, 2H), 5.89 (d, J=19.0 Hz, 1H), 4.37 (d,J=8.8 Hz, 2H), 4.01-3.61 (m, 2H), 3.53-3.40 (m, 1H), 3.38-3.17 (m, 1H),3.07-2.88 (m, 1H), 2.71-2.59 (m, 2H), 2.52-2.42 (m, 2H), 2.21-2.00 (m,2H), 1.91-1.82 (m, 1H), 1.50-1.34 (m, 1H), 1.05-0.98 (m, 1H), 0.97-0.91(m, 2H), 0.75 (q, J=5.2 Hz, 1H), 0.68-0.63 (m, 2H).

Example 67:(rac)-(2s,4s)-2-(6-(3-Chloro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-3-chloro-4-methylbenzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₀H₂₃ClN₂O₃, 374.1; m/z found, 375.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.20 (dd, J=6.3, 1.8 Hz, 1H), 7.14 (d, J=7.9 Hz, 1H), 7.01 (dt, J=7.8,2.2 Hz, 1H), 5.83 (d, J=20.5 Hz, 1H), 4.37 (d, J=8.3 Hz, 2H), 4.01-3.87(m, 1H), 3.73 (ddd, J=15.3, 13.2, 3.3 Hz, 1H), 3.58-3.40 (m, 1H),3.37-3.17 (m, 1H), 3.08-2.91 (m, 1H), 2.70-2.60 (m, 2H), 2.54-2.44 (m,2H), 2.33 (s, 3H), 2.21-1.99 (m, 2H), 1.50-1.34 (m, 1H), 1.06-0.99 (m,1H), 0.81-0.73 (m, 1H).

Example 68:(rac)-(2r,4s)-2-(6-(3-Chloro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-3-chloro-4-methylbenzene instead of1-bromo-4-(tert-butyl)benzene in Step A and using(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₁H₂₅ClN₂O₂,372.2; m/z found, 373.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (s,1H), 7.25 (dd, J=4.6, 2.8 Hz, 2H), 7.11 (dt, J=7.9, 1.5 Hz, 1H),3.90-3.54 (m, 2H), 3.31-3.18 (m, 2H), 3.10-2.95 (m, 1H), 2.33-2.24 (m,5H), 2.23-2.16 (m, 2H), 2.16-2.10 (m, 4H), 2.06-1.94 (m, 2H), 1.49-1.36(m, 1H), 1.01-0.90 (m, 1H), 0.76 (t, J=5.3 Hz, 1H).

Example 69:(rac)-(2s,4s)-2-(6-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-4-(1-methylcyclopropyl)benzeneinstead of 1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): masscalcd. for C₂₃H₂₈N₂O₃, 380.2; m/z found, 381.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.21-7.10 (m, 4H), 5.84 (d, J=19.3 Hz, 1H), 4.37 (d, J=8.6 Hz,2H), 4.02-3.60 (m, 2H), 3.47 (t, J=6.4 Hz, 1H), 3.39-3.16 (m, 1H),3.09-2.90 (m, 1H), 2.74-2.59 (m, 2H), 2.57-2.42 (m, 2H), 2.23-1.97 (m,2H), 1.50-1.43 (m, 1H), 1.38 (s, 3H), 1.07-1.00 (m, 1H), 0.86-0.80 (m,2H), 0.79-0.74 (m, 1H), 0.71 (dd, J=6.1, 4.2 Hz, 2H).

Example 70:(rac)-(2r,4s)-2-(6-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-4-(1-methylcyclopropyl)benzeneinstead of 1-bromo-4-(tert-butyl)benzene in Step A and using(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): MASS CALCD. FOR C₂₄H₃₀N₂O₂, 378.2;M/Z FOUND, 379.2 [M+H]⁺. ¹H NMR (400 MHZ, DMSO-d₆) δ 7.91 (s, 1H), 7.11(s, 4H), 3.89-3.60 (m, 2H), 3.26-3.16 (m, 2H), 3.07-2.92 (m, 1H),2.32-2.23 (m, 2H), 2.23-2.08 (m, 6H), 2.04-1.88 (m, 2H), 1.39-1.27 (m,4H), 0.95-0.87 (m, 1H), 0.80-0.64 (m, 5H).

Example 71:(rac)-(2s,4s)-2-(6-(3-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-3-(1-methylcyclopropyl)benzeneinstead of 1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): masscalcd. for C₂₃H₂₈N₂O₃, 380.2; m/z found, 381.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.21 (t, J=7.6 Hz, 1H), 7.14-7.07 (m, 2H), 7.06-6.99 (m, 1H),5.85 (d, J=19.7 Hz, 1H), 4.38 (d, J=8.8 Hz, 2H), 4.02-3.64 (m, 2H),3.51-3.46 (m, 1H), 3.40-3.19 (m, 1H), 3.07-2.93 (m, 1H), 2.72-2.60 (m,2H), 2.56-2.43 (m, 2H), 2.24-2.04 (m, 2H), 1.52-1.41 (m, 1H), 1.39 (s,3H), 1.10-0.99 (m, 1H), 0.86-0.82 (m, 2H), 0.78 (q, J=5.4 Hz, 1H), 0.72(dd, J=6.1, 4.2 Hz, 2H).

Example 72:(rac)-(2s,4s)-2-(6-(4-Cyclopropyl-2-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-4-cyclopropyl-2-methylbenzene insteadof 1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₃H₂₈N₂O₃, 380.2; m/z found, 381.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.06 (dd, J=7.8, 4.1 Hz, 1H), 6.86 (s, 1H), 6.82 (d, J=7.8 Hz, 1H), 5.78(d, J=24.4 Hz, 1H), 4.37 (d, J=12.7 Hz, 2H), 4.00-3.94 (m, 1H),3.89-3.59 (m, 2H), 3.36-3.16 (m, 1H), 3.11-2.90 (m, 1H), 2.72-2.59 (m,2H), 2.55-2.43 (m, 2H), 2.34 (s, 3H), 2.05-1.77 (m, 3H), 1.44-1.29 (m,1H), 1.00-0.88 (m, 3H), 0.71 (dd, J=8.9, 5.1 Hz, 1H), 0.67-0.61 (m, 2H).

Example 73:(rac)-(2s,4s)-2-(6-(3-Isopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-3-isopropylbenzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₂H₂₈N₂O₃, 368.2; m/z found, 369.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.25-7.20 (m, 1H), 7.10-7.02 (m, 3H), 5.77 (d, J=21.2 Hz, 1H), 4.37 (d,J=8.9 Hz, 2H), 4.03-3.63 (m, 2H), 3.53-3.46 (m, 1H), 3.42-3.17 (m, 1H),3.10-2.94 (m, 1H), 2.92-2.83 (m, 1H), 2.71-2.60 (m, 2H), 2.57-2.44 (m,2H), 2.24-2.02 (m, 2H), 1.54-1.38 (m, 1H), 1.24 (d, J=6.9 Hz, 6H),1.09-1.03 (m, 1H), 0.78 (q, J=5.2 Hz, 1H).

Example 74:(rac)-(2s,4s)-2-(6-(4-Isopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 1-bromo-4-isopropylbenzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₂₂H₂₈N₂O₃, 368.2; m/z found, 369.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.20-7.12 (m, 4H), 5.90 (d, J=18.9 Hz, 1H), 4.37 (d, J=8.5 Hz, 2H),4.05-3.61 (m, 2H), 3.48 (t, J=6.4 Hz, 1H), 3.40-3.16 (m, 1H), 3.06-2.93(m, 1H), 2.91-2.83 (m, 1H), 2.74-2.59 (m, 2H), 2.56-2.41 (m, 2H),2.24-2.00 (m, 2H), 1.53-1.35 (m, 1H), 1.23 (d, J=6.9 Hz, 6H), 1.10-1.01(m, 1H), 0.77 (q, J=5.3 Hz, 1H).

Example 75:(rac)-(2s,4s)-2-(6-(4-Methyl-3-(trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 4-bromo-1-methyl-2-(trifluoromethoxy)benzene(Intermediate 8) instead of 1-bromo-4-(tert-butyl)benzene in Step A. MS(ESI): mass calcd. for C₂₁H₂₃F₃N₂O₄, 424.2; m/z found, 425.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.17 (d, J=7.9 Hz, 1H), 7.07-7.01 (m, 2H), 5.93(d, J=18.5 Hz, 1H), 4.37 (d, J=8.2 Hz, 2H), 4.02-3.63 (m, 2H), 3.55-3.43(m, 1H), 3.40-3.19 (m, 1H), 3.08-2.90 (m, 1H), 2.72-2.60 (m, 2H),2.56-2.42 (m, 2H), 2.27 (s, 3H), 2.20-2.03 (m, 2H), 1.52-1.36 (m, 1H),1.07-0.97 (m, 1H), 0.85-0.75 (m, 1H).

Example 76:(rac)-(2r,4s)-2-(6-(4-Methyl-3-(trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)trifluoroborate(Intermediate 6) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using 4-bromo-1-methyl-2-(trifluoromethoxy)benzene(Intermediate 8) instead of 1-bromo-4-(tert-butyl)benzene in Step A andusing (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 4) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₂H₂₅F₃N₂O₃,422.2; m/z found, 423.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (s,1H), 7.30 (d, J=8.1 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.11 (s, 1H),3.89-3.56 (m, 2H), 3.42-3.37 (m, 1H), 3.28-3.20 (m, 1H), 3.09-2.94 (m,1H), 2.35-2.25 (m, 2H), 2.24-2.16 (m, 5H), 2.16-2.10 (m, 4H), 2.07-1.97(m, 2H), 1.49-1.38 (m, 1H), 1.01-0.92 (m, 1H), 0.84-0.76 (m, 1H).

Example 77:(rac)-(2s,4s)-2-(1-Phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 usingpotassium(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-1-yl)trifluoroborate(Intermediate 7) instead of potassium(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate(Intermediate 5) and using bromobenzene instead of1-bromo-4-(tert-butyl)benzene in Step A. MS (ESI): mass calcd. forC₁₉H₂₂N₂O₃, 326.2; m/z found, 327.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.37-7.27 (m, 3H), 7.26-7.19 (m, 2H), 5.81 (d, J=16.9 Hz, 1H), 4.53-4.30(m, 2H), 4.00-3.40 (m, 3H), 3.25-2.86 (m, 2H), 2.75-2.32 (m, 4H),2.25-2.13 (m, 1H), 1.91-1.73 (m, 1H), 1.46-1.31 (m, 1H), 1.14-1.04 (m,1H), 0.63 (dd, J=9.7, 5.1 Hz, 1H).

Example 78:(2s,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: (3-(tert-Butyl)benzylidene)hydrazine. To hydrazine monohydrate(21.3 mL, 449 mmol) was added 3-tert-butylbenzaldehyde (7.1 g, 44 mmol)dropwise over 1 min at room temperature and the reaction mixture wasstirred at room temperature for 20 min. The reaction mixture was pouredinto water and extracted with Et₂O. The combined organic layers werewashed with water, dried over magnesium sulfate, filtered and evaporatedunder reduced pressure to give the title compound (7.3 g, 94% yield) asa yellow oil which was used without further purification in the nextstep. MS (ESI): mass calcd. for C₁₁H₁₆N₂, 176.1; m/z found, 177.2[M+H]⁺.

Step B:(1R,5S,6s)-3-Benzyl-6-(3-(tert-butyl)phenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione.To a solution of (3-(tert-butyl)benzylidene)hydrazine (7.3 g, 41 mmol)in 1,4-dioxane (70 mL) was added manganese(IV) oxide (15.1 g, 173 mmol)and the reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was filtered through a pad of Celite®. To the filtratewas added N-benzylmaleimide (7.7 g, 41 mmol) and the reaction mixturewas stirred at 100° C. for 16 h. The reaction mixture was evaporatedunder reduced pressure and the residue was triturated with Et₂O to givethe title compound (3.6 g, 26% yield) as a white powder. MS (ESI): masscalcd. for C₂₂H₂₃NO₂, 333.2; m/z found, 334.2 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 7.38-7.32 (m, 2H), 7.32-7.27 (m, 3H), 7.27-7.21 (m, 3H),7.00-6.94 (m, 1H), 4.45 (s, 2H), 3.14-3.08 (m, 2H), 3.08-3.03 (m, 1H),1.27 (s, 9H).

Step C:(1R,5S,6s)-3-Benzyl-6-(3-(tert-butyl)phenyl)-3-azabicyclo[3.1.0]hexane.To a suspension of(1R,5S,6s)-3-benzyl-6-(3-(tert-butyl)phenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione(3.5 g, 11 mmol) in freshly distilled THF (10 mL) was added lithiumaluminum hydride (LiAlH₄) (42 mL, 1 M in THF) dropwise at 0° C. over 10min and the reaction mixture was stirred at 0° C. for 1 h under argon.The reaction mixture was allowed to warm to room temperature and stirredat room temperature for 16 h under argon. The reaction mixture wasdiluted with Et₂O and the reaction was quenched with sodium sulfatedecahydrate. The mixture was filtered and the solid was washed withEtOAc. The combined filtrates were evaporated under reduced pressure andthe residue was purified by FCC on silica (0-30% EtOAc in heptane) togive the title compound (1.7 g, 53% yield) as a white crystalline solid.MS (ESI): mass calcd. for C₂₂H₂₇N, 305.2; m/z found, 306.5 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 7.37-7.28 (m, 4H), 7.27-7.21 (m, 1H), 7.16-7.11(m, 2H), 7.11-7.09 (m, 1H), 6.81-6.73 (m, 1H), 3.61 (s, 2H), 3.02 (d,J=8.9 Hz, 2H), 2.45-2.41 (m, 2H), 2.26-2.22 (m, 1H), 1.70-1.65 (m, 2H),1.25 (s, 9H).

Step D: (1R,5S,6s)-6-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexanehydrochloride. To a solution of(1R,5S,6s)-3-benzyl-6-(3-(tert-butyl)phenyl)-3-azabicyclo[3.1.0]hexane(1.66 g, 5.43 mmol) in EtOH (15 mL) was added 10% Pd/C (580 mg, 0.54mmol) and hydrogen chloride (HCl) (4.2 M in 1,4-dioxane, 3.9 mL). Thereaction mixture was stirred at room temperature for 16 h under H₂ (1bar). The reaction mixture was filtered through a pad of Celite®. To thefiltrate was added 10% Pd/C (580 mg, 0.54 mmol) and the reaction mixturewas stirred at room temperature for 72 h under H₂ (1 bar). The reactionmixture was filtered through a pad of Celite® and the Celite® was washedwith EtOH. The combined filtrates were evaporated under reduced pressureand the product was triturated with Et₂O to give the title compound (940mg, 69% yield) as a white powder. MS (ESI): mass calcd. for C₁₅H₂₁N,215.2; m/z found, 216.3 [M+H]⁺.

Step E:(2s,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.To a suspension of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 205 mg, 1.2 mmol) in DCM (5 mL) was added EDC (229 mg,1.19 mmol), TEA (670 μL, 4.81 mmol) and HOBt (178 mg, 1.32 mmol). Thereaction mixture was stirred at room temperature for 10 min. To thereaction mixture was added(1R,5S,6s)-6-(3-(tert-butyl)phenyl)-3-azabicyclo[3.1.0]hexanehydrochloride (300 mg, 1.19 mmol) and stirred at room temperature for 18h. The reaction mixture was diluted with DCM and washed with 1 Mpotassium bisulfate, saturated NaHCO₃ and brine. The organic layer wasdried over magnesium sulfate, filtered and evaporated under reducedpressure. The crude product was purified by preparative HPLC to give thetitle compound (235 mg, 54% yield) as a white powder. MS (ESI): masscalcd. for C₂₂H₂₈N₂O₃, 368.2; m/z found, 369.2 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.07 (s, 1H), 7.20-7.14 (m, 2H), 7.13-7.10 (m, 1H), 6.83-6.77(m, 1H), 4.37 (d, J=9.3 Hz, 1H), 4.35 (d, J=9.3 Hz, 1H), 3.74 (d, J=11.9Hz, 1H), 3.68 (d, J=10.5 Hz, 1H), 3.55 (dd, J=10.5, 4.3 Hz, 1H), 3.36(dd, J=11.9, 4.4 Hz, 1H), 2.94-2.83 (m, 1H), 2.44-2.27 (m, 4H),1.95-1.90 (m, 1H), 1.88-1.82 (m, 1H), 1.64-1.59 (m, 1H), 1.25 (s, 9H).

Example 79:(2r,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 78using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 4) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step E. MS (ESI): mass calcd. for C₂₃H₃₀N₂O₂, 366.2;m/z found, 367.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.23-7.17 (m,2H), 7.08 (dd, J=2.0, 1.0 Hz, 1H), 6.81-6.75 (m, 1H), 6.56 (s, 1H), 3.97(d, J=12.1 Hz, 1H), 3.72-3.58 (m, 2H), 3.54 (dd, J=12.2, 3.9 Hz, 1H),2.89 (p, J=8.3 Hz, 1H), 2.61-2.50 (m, 2H), 2.43-2.31 (m, 4H), 2.25-2.17(m, 2H), 1.88 (hept, J=3.7 Hz, 2H), 1.63 (t, J=3.5 Hz, 1H), 1.30 (s,9H).

Example 80:(2s,4S)-2-((1R,5S,6S)-6-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 78using 4-trifluoromethylbenzaldehyde instead of 3-tert-butylbenzaldehydein Step A. MS (ESI): mass calcd. for C₁₉H₁₉F₃N₂O₃, 380.1; m/z found,381.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.07 (s, 1H), 7.59 (d, J=8.1Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 4.37 (d, J=8.7 Hz, 1H), 4.35 (d, J=8.8Hz, 1H), 3.77 (d, J=12.0 Hz, 1H), 3.71 (d, J=10.6 Hz, 1H), 3.57 (dd,J=10.6, 4.3 Hz, 1H), 3.39 (dd, J=12.0, 4.4 Hz, 1H), 2.94-2.85 (m, 1H),2.45-2.38 (m, 1H), 2.37-2.26 (m, 3H), 2.08-2.02 (m, 1H), 1.99-1.95 (m,1H), 1.80-1.76 (m, 1H).

Example 81:(2r,4S)-2-((1R,5S,6S)-6-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 78using 4-trifluoromethylbenzaldehyde instead of 3-tert-butylbenzaldehydein Step A and using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 4) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step E. MS (ESI): mass calcd. for C₂₀H₂₁F₃N₂O₂,378.2; m/z found, 379.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.95 (s,1H), 7.59 (d, J=8.1 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 3.77 (d, J=12.0 Hz,1H), 3.73 (d, J=10.6 Hz, 1H), 3.58 (dd, J=10.6, 4.2 Hz, 1H), 3.38 (dd,J=12.0, 4.3 Hz, 1H), 2.96-2.86 (m, 1H), 2.37-2.30 (m, 1H), 2.29-2.23 (m,1H), 2.22-2.17 (m, 2H), 2.16-2.09 (m, 4H), 2.06-2.01 (m, 1H), 1.99-1.93(m, 1H), 1.81-1.75 (m, 1H).

Example 82:(2s,4S)-2-((1R,5S,6S)-6-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 78using 4-tert-butylbenzaldehyde instead of 3-tert-butylbenzaldehyde inStep A. MS (ESI): mass calcd. for C₂₂H₂₈N₂O₃, 368.2; m/z found, 369.2[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.06 (s, 1H), 7.30-7.21 (m, 2H),7.03-6.94 (m, 2H), 4.37 (d, J=9.1 Hz, 1H), 4.35 (d, J=9.0 Hz, 1H), 3.73(d, J=11.9 Hz, 1H), 3.67 (d, J=10.5 Hz, 1H), 3.54 (dd, J=10.5, 4.3 Hz,1H), 3.36 (dd, J=11.9, 4.5 Hz, 1H), 2.94-2.84 (m, 1H), 2.44-2.37 (m,1H), 2.37-2.27 (m, 3H), 1.93-1.86 (m, 1H), 1.85-1.78 (m, 1H), 1.59-1.54(m, 1H), 1.24 (s, 9H).

Example 83:(2r,4S)-2-((1R,5S,6S)-6-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 78using 4-tert-butylbenzaldehyde instead of 3-tert-butylbenzaldehyde inStep A and using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 4) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step E. MS (ESI): mass calcd. for C₂₃H₃₀N₂O₂, 366.2;m/z found, 367.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.93 (s, 1H),7.25-7.20 (m, 2H), 7.00-6.92 (m, 2H), 3.70 (d, J=11.9 Hz, 1H), 3.67 (d,J=10.5 Hz, 1H), 3.53 (dd, J=10.5, 4.3 Hz, 1H), 3.33 (dd, J=11.9, 4.4 Hz,1H), 2.94-2.83 (m, 1H), 2.32-2.26 (m, 1H), 2.26-2.20 (m, 1H), 2.20-2.04(m, 6H), 1.90-1.83 (m, 1H), 1.82-1.75 (m, 1H), 1.57-1.51 (m, 1H), 1.21(s, 9H).

Example 84:(2s,4S)-2-((1R,5S,6S)-6-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 78using 3-isopropylbenzaldehyde instead of 3-tert-butylbenzaldehyde inStep A. MS (ESI): mass calcd. for C₂₁H₂₆N₂O₃, 354.2; m/z found, 355.2[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.05 (s, 1H), 7.13 (t, J=7.6 Hz,1H), 7.00-6.96 (m, 1H), 6.95-6.91 (m, 1H), 6.83-6.77 (m, 1H), 4.35 (d,J=9.2 Hz, 1H), 4.32 (d, J=9.0 Hz, 1H), 3.71 (d, J=12.0 Hz, 1H), 3.65 (d,J=10.5 Hz, 1H), 3.52 (dd, J=10.5, 4.3 Hz, 1H), 3.34 (dd, J=11.9, 4.4 Hz,1H), 2.91-2.75 (m, 2H), 2.41-2.23 (m, 4H), 1.92-1.87 (m, 1H), 1.85-1.79(m, 1H), 1.58-1.54 (m, 1H), 1.15 (d, J=6.9 Hz, 6H).

Example 85:(2s,4S)-2-((1R,5S,6S)-6-(4-Methyl-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 78using 4-methyl-3-trifluoromethylbenzaldehyde instead of3-tert-butylbenzaldehyde in Step A. MS (ESI): mass calcd. forC₂₀H₂₁N₂O₃, 394.2; m/z found, 395.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.07 (s, 1H), 7.40-7.36 (m, 1H), 7.31 (d, J=7.9 Hz, 1H), 7.25-7.20 (m,1H), 4.38 (d, J=9.2 Hz, 1H), 4.34 (d, J=9.1 Hz, 1H), 3.75 (d, J=11.9 Hz,1H), 3.68 (d, J=10.5 Hz, 1H), 3.55 (dd, J=10.6, 4.3 Hz, 1H), 3.36 (dd,J=12.0, 4.4 Hz, 1H), 2.93-2.82 (m, 1H), 2.39-2.36 (m, 3H), 2.43-2.27 (m,4H), 2.02-1.97 (m, 1H), 1.94-1.89 (m, 1H), 1.77-1.72 (m, 1H).

Example 86:(2s,4S)-2-((1R,5S,6S)-6-(4-Ethylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: N′-(4-Ethylbenzylidene)-4-methylbenzenesulfonohydrazide. To asolution of 4-ethylbenzaldehyde (2.0 g, 15 mmol) in THF (40 mL) wasadded 4-methylbenzenesulfonhydrazide (2.8 g, 15 mmol) and the reactionstirred at room temperature for 3 h. Na₂SO₄ was added, the mixture wasfiltered, and the filtrate was concentrated under reduced pressure toafford the title compound as a white solid in quantitative yield. MS(ESI): mass calcd. for C₁₆H₁₈N₂O₂S, 302.1; m/z found, 302.9 [M+H]⁺.

Step B: (1R,5S,6s)-3-Benzyl-6-(4-ethylphenyl)-3-azabicyclo[3.1.0]hexane.To a solution of N′-(4-ethylbenzylidene)-4-methylbenzenesulfonohydrazide(500 mg, 1.65 mmol) in THF (30 mL) was added NaH (60% dispersion inmineral oil, 80 mg, 2.00 mmol). The reaction was then heated withstirring at 60° C. for 1 h whereupon the reaction turned into a redslurry. After cooling to room temperature, the mixture was filtered, andthe filtrate carefully concentrated in vacuo using a room temperaturewater bath to yield crude diazo intermediate. The crude residue was thendissolved in DCM (15 mL) and the solution added dropwise over 15 minutesto a stirring mixture of 1-benzyl-2,5-dihydro-1H-pyrrole (195 mg, 1.22mmol) and ZnI₂ (41 mg, 0.13 mmol) in DCM (50 mL). Mild exotherm and gasevolution occurred during the addition. The reaction was stirred at roomtemperature for 1 h then quenched with H₂O and brine. The aqueous layerwas extracted with EtOAc. The combined organic layers were dried overNa₂SO₄, filtered, and the filtrate concentrated under reduced pressureto give crude product. The crude oil was purified via FCC on silica (5%EtOAc in hexane) to afford the title compound (256 mg, 75% yield). MS(ESI): mass calcd. for C₂₀H₂₃N, 277.2; m/z found, 278.1 [M+H]⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 7.36-7.28 (m, 5H), 7.06-7.04 (d, J=8.1 Hz, 2H),6.96-6.94 (d, J=8.2 Hz, 2H), 3.61 (s, 2H), 3.02-3.0 (d, J=8.9 Hz, 2H),2.55-2.51 (m, 2H), 2.46-2.40 (br s, 2H), 2.21 (t, J=3.3 Hz, 1H), 1.64(s, 2H), 1.13 (t, J=7.6 Hz, 3H).

Step C: (1R,5S,6s)-6-(4-Ethylphenyl)-3-azabicyclo[3.1.0]hexane.(1R,5S,6s)-3-Benzyl-6-(4-ethylphenyl)-3-azabicyclo[3.1.0]hexane (50 mg,0.18 mmol) was taken up in EtOH (1.8 mL). 10% Pd/C (19 mg, 0.02 mmol)was added and the reaction vessel was evacuated and left under a H₂balloon to stir at rt for 16 h. The reaction mixture was filteredthrough Celite® with MeOH and concentrated under reduced pressure. Thetitle compound was used without further purification in the next step.MS (ESI): mass calcd. for C₁₃H₁₇N, 187.1; m/z found, 188.1 [M+H]⁺.

Step D:(2s,4S)-2-((1R,5S,6S)-6-(4-Ethylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.(1R,5S,6s)-6-(4-Ethylphenyl)-3-azabicyclo[3.1.0]hexane (16 mg, 0.085mmol) and (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 16 mg, 0.094 mmol) were taken up in DMF (0.6 mL). DIPEA(37 μL, 0.214 mmol) and HATU (37 mg, 0.094 mmol) were added and thereaction was stirred at rt for 2 h. The reaction mixture was filteredthrough a PTFE filter with MeOH and purified via reverse phase HPLC(5-95% ACN in 20 mM NH₄OH in water) to afford the title compound (12 mg,41% yield). MS (ESI): mass calcd. for C₂₀H₂₄N₂O₃, 340.2; m/z found,341.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ7.14-7.08 (m, 2H),6.97-6.91 (m, 2H), 6.31 (s, 1H), 4.36 (s, 2H), 3.97 (d, J=12.2 Hz, 1H),3.65 (t, J=2.1 Hz, 2H), 3.56 (dd, J=12.1, 3.7 Hz, 1H), 2.87 (tt, J=8.4,7.2 Hz, 1H), 2.71-2.56 (m, 4H), 2.53-2.43 (m, 2H), 1.91-1.83 (m, 2H),1.61 (t, J=3.6 Hz, 1H), 1.21 (t, J 7.6 Hz, 3H).

Example 87:(2r,4S)-2-((1R,5S,6S)-6-(4-Ethylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 86using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 4) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step D. MS (ESI): mass calcd. for C₂₁H₂₆N₂O₂, 338.2;m/z found, 339.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.14-7.08 (m,2H), 6.97-6.90 (m, 2H), 6.22 (s, 1H), 3.96 (d, J=12.2 Hz, 1H), 3.71-3.58(m, 2H), 3.52 (dd, J=12.1, 4.0 Hz, 1H), 2.89 (p, J=8.2 Hz, 1H),2.65-2.46 (m, 4H), 2.43-2.31 (m, 4H), 2.26-2.17 (m, 2H), 1.90-1.81 (m,2H), 1.60 (t, J=3.5 Hz, 1H), 1.21 (t, J=7.6 Hz, 3H).

Example 88:(2s,4S)-2-((1R,5S,6S)-6-(3,4-Dimethylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 86using 3,4-dimethylbenzaldehyde instead of 4-ethylbenzaldehyde in Step A.MS (ESI): mass calcd. for C₂₀H₂₄N₂O₃, 340.2; m/z found, 341.2 [M+H]⁺. ¹HNMR (500 MHz, Chloroform-d) δ 7.03 (d, J 7.7 Hz, 1H), 6.81 (d, J=2.0 Hz,1H), 6.75 (dd, J=7.8, 2.0 Hz, 1H), 6.26 (s, 1H), 4.36 (s, 2H), 3.96 (d,J=12.2 Hz, 1H), 3.64 (t, J=2.4 Hz, 2H), 3.55 (dd, J=12.2, 3.6 Hz, 1H),2.87 (tt, J=8.5, 7.2 Hz, 1H), 2.70-2.58 (m, 2H), 2.52-2.42 (m, 2H), 2.22(s, 3H), 2.22 (s, 3H), 1.86 (q, J=3.1 Hz, 2H), 1.58 (t, J=3.5 Hz, 1H).

Example 89:(2r,4S)-2-((1R,5S,6S)-6-(3,4-Dimethylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 86using 3,4-dimethylbenzaldehyde instead of 4-ethylbenzaldehyde in Step Aand using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 4) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step D. MS (ESI): mass calcd. for C₂₁H₂₆N₂O₂, 338.2;m/z found, 339.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) δ 7.02 (d, J 7.7Hz, 1H), 6.80 (d, J=1.9 Hz, 1H), 6.75 (dd, J=7.8, 2.0 Hz, 1H), 6.32 (s,1H), 3.95 (d, J=12.2 Hz, 1H), 3.67 (d, J=10.1 Hz, 1H), 3.62 (dd, J=10.2,3.8 Hz, 1H), 3.52 (dd, J=12.1, 4.1 Hz, 1H), 2.89 (p, J=8.3 Hz, 1H),2.58-2.47 (m, 2H), 2.41-2.30 (m, 4H), 2.23-2.18 (m, 8H), 1.88-1.81 (m,2H), 1.57 (t, J=3.5 Hz, 1H).

Example 90:(2s,4S)-2-((1R,5S,6S)-6-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 86using 4-isopropylbenzaldehyde instead of 4-ethylbenzaldehyde in Step A.MS (ESI): mass calcd. for C₂₁H₂₆N₂O₃, 354.2; m/z found, 355.2 [M+H]⁺. ¹HNMR (400 MHz, Chloroform-d) δ 7.16-7.11 (m, 2H), 6.98-6.93 (m, 2H), 6.30(s, 1H), 4.36 (s, 2H), 3.96 (d, J=12.2 Hz, 1H), 3.68-3.61 (m, 2H), 3.56(dd, J=12.2, 3.6 Hz, 1H), 2.92-2.80 (m, 2H), 2.70-2.60 (m, 2H),2.53-2.43 (m, 2H), 1.92-1.84 (m, 2H), 1.61 (t, J=3.6 Hz, 1H), 1.22 (d,J=6.9 Hz, 6H).

Example 91:(2r,4S)-2-((1R,5S,6S)-6-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 86using 4-isopropylbenzaldehyde instead of 4-ethylbenzaldehyde in Step Aand using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 4) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step D. MS (ESI): mass calcd. for C₂₂H₂₈N₂O₂, 352.2;m/z found, 353.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.16-7.11 (m,2H), 6.97-6.93 (m, 2H), 6.17 (s, 1H), 3.96 (d, J=12.1 Hz, 1H), 3.70-3.59(m, 2H), 3.53 (dd, J=12.2, 4.0 Hz, 1H), 2.94-2.81 (m, 2H), 2.58-2.47 (m,2H), 2.44-2.31 (m, 4H), 2.25-2.17 (m, 2H), 1.90-1.81 (m, 2H), 1.60 (t,J=3.5 Hz, 1H), 1.22 (d, J=6.9 Hz, 6H).

Example 92:(2s,4S)-2-((1R,5S,6S)-6-(2,3-Dihydro-1H-inden-5-yl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 86using 2,3-dihydro-1H-indene-5-carbaldehyde instead of4-ethylbenzaldehyde in Step A. MS (ESI): mass calcd. for C₂₂H₂₄N₂O₃,352.2; m/z found, 353.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.12(d, J 7.6 Hz, 1H), 6.89 (d, J=1.7 Hz, 1H), 6.80 (dd, J=7.7, 1.7 Hz, 1H),6.41 (s, 1H), 4.36 (s, 2H), 3.96 (d, J=12.2 Hz, 1H), 3.65 (t, J=2.1 Hz,2H), 3.55 (dd, J=12.2, 3.5 Hz, 1H), 2.86 (td, J=7.4, 3.7 Hz, 5H),2.71-2.59 (m, 2H), 2.53-2.41 (m, 2H), 2.05 (p, J=7.4 Hz, 2H), 1.90-1.83(m, 2H), 1.61 (t, J=3.6 Hz, 1H).

Example 93:(rac)-(2s,4*5)-2-((1*R,5*S,6*R)-6-(3-(tert-Butyl)phenyl)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 86using 3-tert-butylbenzaldehyde instead of 4-ethylbenzaldehyde in Step Aand using 1-benzyl-3-methyl-2,5-dihydro-1H-pyrrole (Intermediate 9)instead of 1-benzyl-2,5-dihydro-1H-pyrrole in Step B. MS (ESI): masscalcd. for C₂₃H₃₀N₂O₃, 382.2; m/z found, 383.3 [M+H]⁺. ¹H NMR (600 MHz,Chloroform-d) δ 7.25-7.20 (m, 2H), 7.13 (dt, J=7.6, 1.8 Hz, 1H),6.92-6.88 (m, 1H), 5.91 (br s, 1H), 4.35 (d, J=9.4 Hz, 2H), 4.00 (dd,J=40.6, 11.9 Hz, 1H), 3.74-3.59 (m, 2H), 3.40 (dd, J=60.1, 9.9 Hz, 1H),2.94-2.84 (m, 1H), 2.69-2.56 (m, 2H), 2.56-2.45 (m, 2H), 1.86-1.79 (m,2H), 1.31 (s, 9H), 1.06 (s, 3H).

Example 94:(rac)-(2s,4s)-2-(1-(4-Ethylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 5 using1-bromo-4-ethylbenzene instead of 1-bromo-4-(tert-butyl)benzene in StepA. MS (ESI): mass calcd. for C₂₀H₂₄N₂O₃, 340.2; m/z found, 341.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 7.21-7.06 (m, 4H), 6.16 (d, J=13.2 Hz, 1H),4.35 (d, J=4.3 Hz, 2H), 4.23-3.94 (m, 1H), 3.85-3.55 (m, 3H), 2.93-2.81(m, 1H), 2.70-2.59 (m, 4H), 2.54-2.39 (m, 2H), 1.94-1.82 (m, 1H), 1.22(td, J=7.6, 1.5 Hz, 3H), 1.18-1.10 (m, 1H), 0.79-0.69 (m, 1H).

Example 95:(2r,4*S)-2-((1*R,5*5)-1-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatographyof Example 26 (Stationary phase: Whelk-O1 (S,S), 5 μm250×21.2 mm, Mobile phase: 0.3% isopropylamine, 60% CO₂, 40% ACN/iPrOH(v/v 50/50)). MS (ESI): mass calcd. for C₂₃H₂₈N₂O₂, 364.2; m/z found,365.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.23-7.16 (m, 2H),7.15-7.05 (m, 2H), 6.15 (s, 1H), 4.23-3.91 (m, 1H), 3.85-3.51 (m, 3H),2.94-2.84 (m, 1H), 2.57-2.45 (m, 2H), 2.44-2.28 (m, 4H), 2.26-2.15 (m,2H), 1.91-1.80 (m, 1H), 1.39 (d, J=1.9 Hz, 3H), 1.12 (dt, J=9.0, 5.0 Hz,1H), 0.87-0.79 (m, 2H), 0.77-0.68 (m, 3H).

Example 96:(2r,4*R)-2-((1*S,5*R)-1-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 26 (Stationary phase: Whelk-O1 (S,S), 5 μm250×21.2 mm, Mobile phase: 0.3% isopropylamine, 60% CO₂, 40% ACN/iPrOH(v/v 50/50)). MS (ESI): mass calcd. for C₂₃H₂₈N₂O₂, 364.2; m/z found,365.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.25-7.16 (m, 2H),7.13-7.05 (m, 2H), 6.10 (s, 1H), 4.23-3.91 (m, 1H), 3.86-3.52 (m, 3H),2.94-2.84 (m, 1H), 2.57-2.45 (m, 2H), 2.44-2.30 (m, 4H), 2.26-2.16 (m,2H), 1.91-1.80 (m, 1H), 1.39 (d, J=1.8 Hz, 3H), 1.12 (dt, J=9.1, 5.1 Hz,1H), 0.87-0.79 (m, 2H), 0.77-0.68 (m, 3H).

Example 97:(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-1-Methyl-6-(o-tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: 4-Methyl-N′-(2-methylbenzylidene)benzenesulfonohydrazide.4-Methylbenzenesulfonhydrazide (3.1 g, 16.6 mmol) was added to asolution of 2-methylbenzaldehyde (2.0 g, 16.6 mmol) in MeOH (40 mL). Thereaction mixture was stirred for 16 hours at room temperature. Theprecipitate was collected by filtration and washed with chilled MeOHbefore drying under reduced pressure to afford the title compound as awhite solid (3.7 g, 77% yield). MS (ESI): mass calcd. for C₁₅H₁₆N₂O₂S288.1; m/z found, 289.1 [M+H]⁺.

Step B:(rac)-(1*R,5*S,6*R)-3-Benzyl-1-methyl-6-(o-tolyl)-3-azabicyclo[3.1.0]hexane.Benzyltriethylammonium chloride (237 mg, 1.04 mmol) was added to amixture of 4-methyl-N′-(2-methylbenzylidene)benzenesulfonohydrazide (1.0g, 3.47 mmol) in aq. NaOH (15%, 8 mL) and toluene (8 mL). The reactionmixture was stirred vigorously at 80° C. for 1 hour. The toluene layerwas separated, washed with sat. aq. NH₄Cl and brine, dried overanhydrous Na₂SO₄, and filtered to obtain 1-(diazomethyl)-2-methylbenzenein toluene (8 mL, crude). This solution was added dropwise over 30minutes to a −10° C. mixture of 1-benzyl-3-methyl-2,5-dihydro-1H-pyrrole(Intermediate 9, 500 mg, 2.89 mmol) and ZnI₂ (923 mg, 2.89 mmol) in DCM(30 mL). The reaction mixture was stirred at room temperature for 16hours before being quenched with water and extracted with DCM. Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered,and concentrated under reduced pressure to afford the crude product,which was purified by FCC (5-13% EtOAc in ether) to afford the titlecompound (480 mg, 60% yield). MS (ESI): mass calcd. for C₂₀H₂₃N, 277.2;m/z found, 278.2 [M+H]⁺.

Step C:(rac)-(1*R,5*S,6*R)-1-Methyl-6-(o-tolyl)-3-azabicyclo[3.1.0]hexane.(1*R,5*S,6*R)-3-Benzyl-1-methyl-6-(o-tolyl)-3-azabicyclo[3.1.0]hexane(430 mg, 1.55 mmol) and dry Pd/C (100 mg, 10 wt. %) were taken up inMeOH (8 mL) and THF (40 mL). The resultant mixture was stirred under H₂(15 psi) at room temperature for 6 hours. The suspension was filteredthrough a pad of Celite® and the pad washed with MeOH. The filtrate wasconcentrated under reduced pressure to afford the title product as ayellow oil (370 mg, crude), which was carried on without furtherpurification. MS (ESI): mass calcd. for C₁₃H₁₇N, 187.1; m/z found, 188.2[M+H]⁺.

Step D:(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-1-Methyl-6-(o-tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.T₃P® (1.2 mL, 50% in ethyl acetate, 2.0 mmol) was added to a solution of(1*R,5*S,6*R)-1-methyl-6-(o-tolyl)-3-azabicyclo[3.1.0]hexane (360 mg,1.9 mmol), (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 200 mg, 1.2 mmol), and DIPEA (1.2 mL, 6.8 mmol) in DCM(5 mL). The reaction was stirred at room temperature for 16 hours beforebeing quenched with H₂O and extracted with DCM. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentratedunder reduced pressure to afford the crude product, which was purifiedby RP-HPLC (40-70% (v/v) CH₃CN in H₂O with 0.05% NH₃+10 mM NH₄HCO₃) toafford the title compound as a white solid (148 mg, 36% yield). MS(ESI): mass calcd. for C₂₀H₂₄N₂O₃, 340.2; m/z found, 341.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.22-7.10 (m, 3H), 7.07-6.98 (m, 1H), 6.16-6.04(m, 1H), 4.38 (d, J=7.3 Hz, 2H), 4.08-3.93 (m, 1H), 3.79-3.62 (m, 2H),3.51-3.38 (m, 1H), 2.96-2.84 (m, 1H), 2.72-2.60 (m, 2H), 2.56-2.45 (m,2H), 2.32-2.26 (m, 3H), 1.92-1.86 (m, 1H), 1.74-1.70 (m, 1H), 0.95 (s,3H).

Example 98:(2s,4S)-2-((1R,5S,6S)-6-(o-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 97using 1-benzyl-2,5-dihydro-1H-pyrrole instead of1-benzyl-3-methyl-2,5-dihydro-1H-pyrrole (Intermediate 9) in Step B. MS(ESI): mass calcd. for C₁₉H₂₂N₂O₃, 326.2; m/z found, 327.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.22-7.08 (m, 3H), 7.00-6.91 (m, 1H), 6.53-6.28(m, 1H), 4.47-4.33 (m, 2H), 4.01 (d, J=12.16 Hz, 1H), 3.73-3.66 (m, 2H),3.60 (dd, J=4.53, 12.16 Hz, 1H), 2.98-2.84 (m, 1H), 2.75-2.60 (m, 2H),2.56-2.46 (m, 2H), 2.37 (s, 3H), 1.98-1.92 (m, 1H), 1.91-1.86 (m, 1H),1.65 (t, J=3.81 Hz, 1H).

Example 99:(2s,4*5)-2-((1*R,5*S,6*R)-6-(3-(tert-Butyl)phenyl)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 93 (Stationary phase: OD-H, 2×25 cm, Mobilephase: 0.1% TEA, 60% CO₂, 40% heptane/iPrOH (v/v 50/50)). MS (ESI): masscalcd. for C₂₃H₃₀N₂O₃, 382.2; m/z found, 383.2 [M+H]⁺. ¹H NMR (600 MHz,Chloroform-d) δ 7.25-7.20 (m, 2H), 7.16-7.10 (m, 1H), 6.93-6.87 (m, 1H),5.97-5.91 (m, 1H), 4.36 (s, 1H), 4.35 (s, 1H), 4.00 (dd, J=40.6, 12.0Hz, 1H), 3.73-3.59 (m, 2H), 3.40 (dd, J=61.4, 11.0 Hz, 1H), 2.95-2.84(m, 1H), 2.68-2.57 (m, 2H), 2.55-2.45 (m, 2H), 1.85-1.79 (m, 2H), 1.31(s, 9H), 1.05 (s, 3H).

Example 100:(2s,4*R)-2-((1*S,5*R,6*5)-6-(3-(tert-Butyl)phenyl)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 93 (Stationary phase: OD-H, 2×25 cm, Mobilephase: 0.1% TEA, 60% CO₂, 40% heptane/iPrOH (v/v 50/50)). MS (ESI): masscalcd. for C₂₃H₃₀N₂O₃, 382.2; m/z found, 383.2 [M+H]⁺. ¹H NMR (600 MHz,Chloroform-d) δ 7.25-7.20 (m, 2H), 7.16-7.10 (m, 1H), 6.93-6.87 (m, 1H),5.97-5.91 (m, 1H), 4.36 (s, 1H), 4.35 (s, 1H), 4.00 (dd, J=40.6, 12.0Hz, 1H), 3.73-3.59 (m, 2H), 3.40 (dd, J=61.4, 11.0 Hz, 1H), 2.95-2.84(m, 1H), 2.68-2.57 (m, 2H), 2.55-2.45 (m, 2H), 1.85-1.79 (m, 2H), 1.31(s, 9H), 1.05 (s, 3H).

Example 101:(2s,4S)-2-((1R,5S,6S)-6-(3-Isobutylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 97using 3-isobutylbenzaldehyde (Intermediate 10) instead of2-methylbenzaldehyde in Step A and 1-benzyl-2,5-dihydro-1H-pyrroleinstead of 1-benzyl-3-methyl-2,5-dihydro-1H-pyrrole (Intermediate 9) inStep B. MS (ESI): mass calcd. for C₂₂H₂₈N₂O₃, 368.2; m/z found, 369.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.14 (m, 1H), 6.97 (d, J=7.5 Hz,1H), 6.87-6.79 (m, 2H), 6.48 (s, 1H), 4.37 (s, 2H), 3.99 (d, J=12.0 Hz,1H), 3.71-3.63 (m, 2H), 3.57 (dd, J=3.5, 12.3 Hz, 1H), 2.94-2.82 (m,1H), 2.74-2.61 (m, 2H), 2.55-2.40 (m, 4H), 1.94-1.82 (m, 3H), 1.64-1.60(m, 1H), 0.90 (d, J=6.5 Hz, 6H).

Example 102:(rac)-(2s,4*5)-2-((1*R,5*S,6*R)-6-(3,4-Dimethylphenyl)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 97using 3,4-dimethylbenzaldehyde instead of 2-methylbenzaldehyde in StepA. MS (ESI): mass calcd. for C₂₁H₂₆N₂O₃, 354.2; m/z found, 355.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 7.06 (d, J=7.6 Hz, 1H), 6.90 (s, 1H),6.86-6.81 (m, 1H), 5.98 (br s, 1H), 4.36 (d, J=6.3 Hz, 2H), 4.03-3.92(m, 1H), 3.74-3.57 (m, 2H), 3.46-3.32 (m, 1H), 2.95-2.84 (m, 1H),2.70-2.57 (m, 2H), 2.57-2.44 (m, 2H), 2.30-2.20 (m, 6H), 1.83-1.73 (m,2H), 1.05 (s, 3H).

Example 103:(2s,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl-5-D)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A:(1R,5S,6s)-3-Benzyl-6-(3-(tert-butyl)-5-iodophenyl)-3-azabicyclo[3.1.0]hexane.The title compound was prepared in a manner analogous to Example 86,Steps A and B using 3-tert-butyl-5-iodobenzaldehy de (Intermediate 13)instead of 4-ethylbenzaldehyde in Step A. MS (ESI): mass calcd. forC₂₂H₂₆IN, 431.1; m/z found, 432.1 [M+H]⁺.

Step B:(1R,5S,6s)-6-(3-(tert-Butyl)-5-iodophenyl)-3-azabicyclo[3.1.0]hexane.(1R,5S,6s)-3-Benzyl-6-(3-(tert-butyl)-5-iodophenyl)-3-azabicyclo[3.1.0]hexane(23 g, 53.3 mmol) and TEA (22 mL, 160 mmol) were taken up in DCM (460mL) under N₂ and cooled to 5° C. To this was added dropwise1-chloroethyl carbonochloridate (23 g, 160 mmol) and the resultingsolution was stirred for 30 min at room temperature. The reactionmixture was concentrated under reduced pressure and diluted in MeOH (230mL). The reaction was stirred for an additional 30 min while heating atreflux. After cooling to rt, the mixture was concentrated under reducedpressure and purified by RP-HPLC to provide the title compound as awhite solid (4.6 g, 25% yield).

Step C:(2s,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)-5-iodophenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 2.54 g, 14.8 mmol), DMF (100 mL), DIPEA (5.9 mL, 33.7mmol), HATU (5.38 g, 14.2 mmol), and(1R,5S,6s)-6-(3-(tert-butyl)-5-iodophenyl)-3-azabicyclo[3.1.0]hexane(4.60 g, 13.5 mmol) were combined under N₂. The resulting solution wasstirred for 1 h at room temperature then quenched with ice water. Thesolids were collected by filtration to provide the title compound as awhite solid (4.8 g, 72% yield). MS (ESI): mass calcd. for C₂₂H₂₇IN₂O₃,494.1; m/z found, 495.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 8.08 (s,1H), 7.47 (t, J=1.6 Hz, 1H), 7.20 (t, J=1.6 Hz, 1H), 7.14 (t, J=1.7 Hz,1H), 4.37 (s, 2H), 3.76 (dd, J=18.9, 11.2 Hz, 2H), 3.55 (dd, J=10.5, 4.1Hz, 1H), 3.51-3.32 (m, 1H), 2.88 (p, J=8.8 Hz, 1H), 2.52-2.32 (m, 4H),1.99 (dt, J=7.4, 3.7 Hz, 1H), 1.91 (dt, J=7.4, 3.7 Hz, 1H), 1.64 (t,J=3.5 Hz, 1H), 1.24 (s, 9H).

Step D:(2s,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl-5-D)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

Method A:(2s,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)-5-iodophenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(150 mg, 0.303 mmol) was taken up in CD₃OD (70 mL) and D-THF (2 mL).This solution was passed through an H-Cube® reactor once (10% Pd/C, 1mL/min, 1 bar) using D₂O to generate D₂. The recovered solution wasconcentrated under reduced pressure. Analysis of the crude material by¹H NMR indicated approximately 93% deuterium incorporation. The crudeproduct was purified via FCC (9/1 EtOAc/hexane) to provide the titlecompound (75 mg, 67% yield).

Method B:(2s,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)-5-iodophenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(20 mg, 0.0404 mmol) was taken up in THF (20 mL) and CD₃OD (10 mL) thenconcentrated under reduced pressure at rt. This was repeated once morebefore the residue was taken up in CD₃OD (20 mL). To this was added Pd/C(30 mg, 10 wt. %) that had been taken up in D₂O and CD₃OD (1:1, 10 mL)and stirred 5 min before filtering off the liquid portion. This wasstirred at rt under an atmosphere of D₂ for 6 h. The reaction solutionwas filtered, and the filtrate was concentrated under reduced pressureat rt. This procedure was repeated seven times. The combined crudeproduct was purified by RP-HPLC (35-65% ACN in water with 0.05% TFAmodifier) to provide the title compound as a light yellow solid (54 mg,52% yield). MS (ESI): mass calcd. for C₂₂H₂₇DN₂O₃, 369.2; m/z found,370.2 [M+H]+. ¹H NMR (500 MHz, Methanol-d₄) δ 7.21-7.17 (m, 1H), 7.13(t, J=1.9 Hz, 1H), 6.84-6.81 (m, 1H), 4.48 (s, 2H), 3.88 (d, J=12.1 Hz,1H), 3.79 (d, J=10.6 Hz, 1H), 3.68 (dd, J=10.5, 4.3 Hz, 1H), 3.51 (dd,J=12.0, 4.5 Hz, 1H), 3.04-2.96 (m, 1H), 2.60-2.51 (m, 2H), 2.51-2.43 (m,2H), 1.99-1.92 (m, 1H), 1.94-1.87 (m, 1H), 1.63 (t, J=3.6 Hz, 1H), 1.30(s, 9H).

Example 104:(2s,4S)-2-((1R,5S,6S)-6-(3-(1-Hydroxy-2-methylpropan-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: (1R,5S,6s)-3-Benzyl-6-(3-bromophenyl)-3-azabicyclo[3.1.0]hexane.The title compound was prepared in a manner analogous to Example 97,Steps A and B using 3-bromobenzaldehyde instead of 2-methylbenzaldehydein Step A and 1-benzyl-2,5-dihydro-1H-pyrrole instead of1-benzyl-3-methyl-2,5-dihydro-1H-pyrrole (Intermediate 9) in Step B. MS(ESI): mass calcd. for C₁₈H₁₈BrN, 327.1; m/z found, 328.1 [M+H]⁺.

Step B: Methyl2-(3-((1R,5S,6s)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl)phenyl)-2-methylpropanoate.(1R,5S,6s)-3-Benzyl-6-(3-bromophenyl)-3-azabicyclo[3.1.0]hexane (1.8 g,5.5 mmol), ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (1.9g, 11.0 mmol), and ZnF₂ (0.17 g, 1.6 mmol) were dissolved in DMF (20mL). The resultant mixture was sparged with N₂ for 5 minutes and thentreated with P(t-Bu)₃ (3.7 g, 2.7 mmol) and Pd₂(dba)₃ (1.0 g, 1.1 mmol).The resultant mixture was sparged with Na for 5 minutes and then stirredwhile heating at 90° C. for 6 hours. After cooling to room temperature,the reaction was quenched with H₂O and extracted with ethyl acetate. Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered,and concentrated under reduced pressure to give the crude product, whichwas purified by FCC (9-25% EtOAc in ether) to afford the title compound(350 mg, 18% yield). MS (ESI): mass calcd. for C₂₃H₂₇NO₂, 349.2; m/zfound, 350.2 [M+H]⁺.

Step C:2-(3-((1R,5S,6s)-3-Benzyl-3-azabicyclo[3.1.0]hexan-6-yl)phenyl)-2-methylpropan-1-ol.LiAlH₄ (65 mg, 1.7 mmol) was added to a −50° C. solution of methyl2-(3-((1R,5S,6s)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl)phenyl)-2-methylpropanoate(300 mg, 0.86 mmol) in THF (10 mL). The resultant mixture was stirred at−50° C. for 3 hours before slowly quenching with H₂O (0.1 mL) and NaOH(15% in water, 0.1 mL). The resultant mixture was stirred at roomtemperature for 30 minutes before additional H₂O (0.3 mL) was added.This was stirred at room temperature for 30 minutes then dried overanhydrous MgSO₄. The suspension was filtered through a pad of Celite®and the pad washed with ethyl acetate. The filtrate was concentratedunder reduced pressure to give the crude product (280 mg, quant.), whichwas used in the next step without further purification. MS (ESI): masscalcd. for C₂₂H₂₇NO, 321.2; m/z found, 322.2 [M+H]⁺.

Step D:2-(3-((1R,5S,6s)-3-Azabicyclo[3.1.0]hexan-6-yl)phenyl)-2-methylpropan-1-ol.2-(3-((1R,5S,6s)-3-Benzyl-3-azabicyclo[3.1.0]hexan-6-yl)phenyl)-2-methylpropan-1-ol(280 mg, 0.871 mmol) and dry Pd/C (150 mg, 10 wt %) were taken up in amixture of THF:MeOH (5:1, 18 mL). The resultant mixture was stirred atroom temperature for 5 hours under H₂ (15 psi). The suspension wasfiltered through a pad of Celite® and the pad washed with THF. Thefiltrate was concentrated under reduced pressure to afford the titleproduct (200 mg, crude), which was used in the next step without furtherpurification.

Step E:(2s,4S)-2-((1R,5S,6S)-6-(3-(1-Hydroxy-2-methylpropan-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.T3P® (825 mg, 50% in ethyl acetate, 1.30 mmol) was added to a solutionof2-(3-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)phenyl)-2-methylpropan-1-ol(200 mg, 0.865 mmol),(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 163 mg, 0.952 mmol), and Et₃N (0.36 mL, 2.59 mmol) inDCM (10 mL). The mixture was stirred at room temperature for 3 hoursbefore being quenched with H₂O and extracted with DCM. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to give the crude product, which waspurified by RP-HPLC (22-52% (v/v) CH₃CN in H₂O with 0.05% ammoniumhydroxide) to afford the title compound as a white solid (46.5 mg, 14%yield). MS (ESI): mass calcd. for C₂₂H₂₈N₂O₄, 384.2; m/z found, 385.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (s, 1H), 7.22-7.07 (m, 3H),6.85-6.75 (m, 1H), 4.62 (t, J=5.4 Hz, 1H), 4.43-4.32 (m, 2H), 3.77-3.66(m, 2H), 3.59-3.52 (m, 1H), 3.41-3.36 (m, 3H), 2.95-2.84 (m, 1H),2.44-2.29 (m, 4H), 1.97-1.79 (m, 2H), 1.65-1.57 (m, 1H), 1.19 (s, 6H).

Example 105:2-Methyl-2-(3-((1R,5S,6S)-3-42s,4S)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)phenyl)propanoicacid

Step A: Methyl2-(3-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)phenyl)-2-methylpropanoate.Methyl2-(3-((1R,5S,6s)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl)phenyl)-2-methylpropanoate(from Example 104, Step B) (330 mg, 0.944 mmol) and dry Pd/C (100 mg, 10wt %) were taken up in a mixture of THF:MeOH (10:1, 22 mL). Theresultant mixture was stirred under H₂ (15 psi) at room temperature for16 hours. The suspension was filtered through a pad of Celite® and thepad washed with THF. The filtrate was concentrated under reducedpressure to afford the title product (250 mg, quant.), which was used inthe next step without further purification. MS (ESI): mass calcd. forC₁₆H₂₁NO₂, 259.2; m/z found, 260.2 [M+H]⁺.

Step B: Methyl2-methyl-2-(3-((1R,5S,6S)-3-((2s,4S)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)phenyl)propanoate.T₃P® (920 mg, 50% in ethyl acetate, 1.45 mmol) was added to a solutionof methyl2-(3-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)phenyl)-2-methylpropanoate(250 mg, 0.964 mmol),(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 165 mg, 0.964 mmol), and Et₃N (0.40 mL, 2.90 mmol) inDCM (10 mL). The mixture was stirred at room temperature for 3 hoursbefore being quenched with H₂O and extracted with DCM. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to give the crude product (300 mg,76% yield), which was used in the next step without furtherpurification. MS (ESI): mass calcd. for C₂₃H₂₈N₂O₅, 412.2; m/z found,413.2 [M+H]⁺.

Step C:2-Methyl-2-(3-((1R,5S,6S)-3-((2s,4S)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)phenyl)propanoicacid. LiOH.H₂O (131 mg, 3.12 mmol) was added to a solution of methyl2-methyl-2-(3-((1R,5S,6S)-3-((2s,4S)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)phenyl)propanoate(280 mg, 0.679 mmol) in 1,4-dioxane (5 mL) and H₂O (5 mL). The resultingmixture was stirred at room temperature for 16 hours before beingquenched with H₂O and washed with ethyl acetate. The aqueous phase wasseparated, adjusted to pH 5-6 with 1 M HCl, and extracted with ethylacetate. The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure to give the crudeproduct, which was purified by RP-HPLC (16-56% (v/v) CH₃CN in H₂O with0.225% HCOOH). Further purification by SFC (DAICEL CHIRALPAK AS 250mm×30 mm, 10 μm; isocratic elution: 30-70% EtOH (containing 0.1% of 25%aq. NH₃) in supercritical CO₂ (v/v)) afforded the title compound as awhite solid (26 mg, 20% yield). MS (ESI): mass calcd. for C₂₂H₂₆N₂O₅,398.2; m/z found, 399.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.27 (br s,1H), 8.09 (s, 1H), 7.24-7.17 (m, 1H), 7.13-7.05 (m, 2H), 6.90-6.83 (m,1H), 4.40-4.33 (m, 2H), 3.78-3.65 (m, 2H), 3.58-3.51 (m, 1H), 3.39-3.38(m, 1H), 2.95-2.83 (m, 1H), 2.44-2.26 (m, 4H), 1.96-1.80 (m, 2H),1.67-1.61 (m, 1H), 1.44 (s, 6H).

Example 106:(rac)-(2s,4*5)-2-((1*R,5*S,6*R)-1-Methyl-6-(3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 97using 3-(trifluoromethyl)benzaldehyde instead of 2-methylbenzaldehyde inStep A. MS (ESI): mass calcd. for C₂₀H₂₁F₃N₂O₃, 394.2; m/z found, 395.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.51-7.46 (m, 1H), 7.45-7.40 (m, 1H),7.39-7.35 (m, 1H), 7.34-7.28 (m, 1H), 6.36-6.27 (m, 1H), 4.37 (d, J=6.0Hz, 2H), 4.07-3.97 (m, 1H), 3.77-3.61 (m, 2H), 3.50-3.34 (m, 1H),2.94-2.83 (m, 1H), 2.72-2.61 (m, 2H), 2.55-2.44 (m, 2H), 1.93-1.86 (m,2H), 1.07-1.03 (m, 3H).

Example 107:(rac)-(2s,4*5)-2-((1*R,5*S,6*R)-1-Methyl-6-(4-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 97using 4-(trifluoromethoxy)benzaldehyde instead of 2-methylbenzaldehydein Step A. MS (ESI): mass calcd. for C₂₀HnF₃N₂O₄, 410.1; m/z found,411.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.19-7.11 (m, 4H), 6.39-6.23 (m,1H), 4.37 (d, J=5.84 Hz, 2H), 4.07-3.94 (m, 1H), 3.76-3.60 (m, 2H),3.50-3.31 (m, 1H), 2.94-2.84 (m, 1H), 2.72-2.61 (m, 2H), 2.55-2.43 (m,2H), 1.87-1.78 (m, 2H), 1.05 (s, 3H).

Example 108:(rac)-(2s,4*5)-2-((1*R,5*S,6*R)-6-(4-Cyclopropylphenyl)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 97using 4-cyclopropylbenzaldehyde instead of 2-methylbenzaldehyde in StepA. MS (ESI): mass calcd. for C₂₂H₂₆N₂O₃, 366.2; m/z found, 367.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 7.09-6.91 (m, 4H), 6.56-6.31 (m, 1H), 4.37 (d,J=6.02 Hz, 2H), 4.04-3.89 (m, 1H), 3.76-3.57 (m, 2H), 3.48-3.29 (m, 1H),2.95-2.79 (m, 1H), 2.75-2.61 (m, 2H), 2.56-2.29 (m, 2H), 1.89-1.84 (m,1H), 1.82-1.76 (m, 2H), 1.03 (s, 3H), 0.98-0.89 (m, 2H), 0.72-0.61 (m,2H).

Example 109:(2s,4S)-2-((1R,5S,6S)-6-(4-Cyclopropyl-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: tert-Butyl(1R,5S,6s)-6-(4-cyclopropyl-2-methylphenyl)-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-carboxylate.The title compound was prepared in a manner analogous to Example 78,Steps A and B using 4-cyclopropyl-2-methylbenzaldehyde (Intermediate 12)instead of 3-tert-butylbenzaldehyde in Step A and tert-butyl2,5-dioxo-2,5-dihydro-1H-pyrrole-1-carboxylate instead ofN-benzylmaleimide in Step B. ¹H NMR (300 MHz, CDCl₃) δ 7.21 (d, J=8.3Hz, 1H), 6.95 (s, 1H), 6.84 (s, 1H), 2.87 (t, J=3.1 Hz, 1H), 2.72 (d,J=3.2 Hz, 2H), 2.40 (s, 3H), 1.90-1.82 (m, 1H), 1.57 (s, 9H), 0.96-0.90(m, 2H), 0.68-0.61 (m, 2H).

Step B:(1R,5S,6s)-6-(4-Cyclopropyl-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione.tert-Butyl(1R,5S,6s)-6-(4-cyclopropyl-2-methylphenyl)-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-carboxylate(560 mg, 1.64 mmol) was taken up in DCM (7 mL) and cooled to 0° C. Tothis was added TFA (1.5 mL, 19.7 mmol) and the mixture was stirred at rtfor 1 h before being concentrated under reduced pressure. The crudeproduct was purified by FCC (0-65% EtOAc in heptane) to yield the titlecompound as a white solid (209 mg, 53% yield). ¹H NMR (300 MHz, CDCl₃) δ7.51 (br s, 1H), 6.91 (s, 1H), 6.85 (s, 2H), 2.90 (t, J=3.0 Hz, 1H),2.71 (d, J=1.5 Hz, 2H), 2.40 (s, 3H), 1.94-1.77 (m, 1H), 0.99-0.88 (m,2H), 0.66 (d, J=5.0 Hz, 2H).

Step C:(1R,5S,6s)-6-(4-Cyclopropyl-2-methylphenyl)-3-azabicyclo[3.1.0]hexane.(1R,5S,6s)-6-(4-Cyclopropyl-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione(209 mg, 0.866 mmol) was taken up in anhydrous THF (5 mL). NaBH₄ (72.1mg, 1.91 mmol) was added and this was stirred at rt for 15 min. BF₃.OEt₂(0.29 mL, 2.34 mmol) was added dropwise and the mixture was heated at50° C. for 16 h. Additional NaBH₄ (32.7 mg, 0.866 mmol) was added andthe mixture was stirred at rt for 15 min. Then, BF₃.OEt₂ (0.11 mL, 0.866mmol) was added and the mixture was stirred at 50° C. for 3 h. Thereaction was cooled to 0° C. and water was added dropwise. Finally, MeOH(15 mL) was added and the mixture was stirred at 100° C. for 16 h. Themixture was concentrated under reduced pressure and purified by FCC(0-80% DCM/MeOH (9:1) in DCM) to yield the title compound as a whitesolid (185 mg, quant.).

Step D:(2s,4S)-2-((1R,5S,6S)-6-(4-Cyclopropyl-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.(1R,5S,6s)-6-(4-Cyclopropyl-2-methylphenyl)-3-azabicyclo[3.1.0]hexane(185 mg, 0.866 mmol) and(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 179 mg, 1.04 mmol) were taken up in DMF (5 mL). To thiswas added T3P® (0.67 mL, 50% in EtOAc, 1.13 mmol) and DIPEA (0.45 mL,2.60 mmol). The mixture was stirred at rt for 1 h. Sat. aq. NaHCO₃ wasadded and the mixture was extracted with EtOAc. The organic layers weredried over MgSO₄, filtered, and concentrated under reduced pressure. Thecrude product was purified by FCC (0-30% DCM/MeOH (20:1) in DCM) toyield the title compound as a white foam (93 mg, 94% yield). MS (ESI):mass calcd. for C₂₂H₂₆N₂O₃, 366.2; m/z found, 367.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 6.88 (s, 1H), 6.86-6.79 (m, 2H), 6.23 (s, 1H), 4.36 (s,2H), 3.98 (d, J=12.2 Hz, 1H), 3.70-3.62 (m, 2H), 3.57 (dd, J=12.2, 4.5Hz, 1H), 2.92-2.84 (m, 1H), 2.71-2.58 (m, 2H), 2.53-2.44 (m, 2H), 2.32(s, 3H), 1.92-1.87 (m, 1H), 1.86-1.78 (m, 2H), 1.58 (t, J=3.8 Hz, 1H),0.96-0.87 (m, 2H), 0.67-0.61 (m, 2H).

Example 110:(2s,4S)-2-((1R,5S,6S)-6-(3-Chloro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 109using 3-chloro-4-methylbenzaldehyde instead of4-cyclopropyl-2-methylbenzaldehyde (Intermediate 12) in Step A. MS(ESI): mass calcd. for C₁₉H₂₁ClN₂O₃, 360.1; m/z found, 361.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.11 (d, J=7.9 Hz, 1H), 6.99 (d, J=1.7 Hz, 1H),6.82 (dd, J=7.8, 1.8 Hz, 1H), 6.10 (s, 1H), 4.36 (s, 2H), 3.97 (d,J=12.3 Hz, 1H), 3.69-3.61 (m, 2H), 3.55 (dd, J=12.3, 3.5 Hz, 1H),2.93-2.82 (m, 1H), 2.69-2.58 (m, 2H), 2.55-2.43 (m, 2H), 2.32 (s, 3H),1.92-1.83 (m, 2H), 1.59 (t, J=3.5 Hz, 1H).

Example 111:(2s,4S)-2-((1R,5S,6S)-6-(3-Ethyl-4-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 97using 3-ethyl-4-fluorobenzaldehyde (Intermediate 11) instead of2-methylbenzaldehyde in Step A and 1-benzyl-2,5-dihydro-1H-pyrroleinstead of 1-benzyl-3-methyl-2,5-dihydro-1H-pyrrole (Intermediate 9) inStep B. MS (ESI): mass calcd. for C₂₀H₂₃FN₂O₃, 358.2; m/z found, 359.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 6.95-6.84 (m, 2H), 6.82-6.76 (m, 1H),6.08 (br s, 1H), 4.37 (s, 2H), 3.98 (d, J=12.2 Hz, 1H), 3.69-3.63 (m,2H), 3.59-3.52 (m, 1H), 2.94-2.84 (m, 1H), 2.69-2.59 (m, 4H), 2.56-2.45(m, 2H), 1.90-1.83 (m, 2H), 1.62-1.59 (m, 1H), 1.22 (t, J=7.6 Hz, 3H).

Example 112:(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-1-Methyl-6-(4-methyl-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 97using 4-methyl-3-(trifluoromethyl)benzaldehyde instead of2-methylbenzaldehyde in Step A. MS (ESI): mass calcd. for C₂₁H₂₃F₃N₂O₃,408.2; m/z found, 409.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.38-7.32 (m,1H), 7.24-7.13 (m, 2H), 6.24-6.13 (m, 1H), 4.37 (d, J=6.0 Hz, 2H), 4.00(dd, J=12.0, 20.0 Hz, 1H), 3.76-3.59 (m, 2H), 3.49-3.33 (m, 1H),2.94-2.83 (m, 1H), 2.72-2.59 (m, 2H), 2.56-2.41 (m, 5H), 1.90-1.79 (m,2H), 1.09-0.99 (m, 3H).

Example 113:(2s,4S)-2-((1R,5S,6S)-6-((2-Methyl-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 97using 2-methyl-3-(trifluoromethyl)benzaldehyde instead of2-methylbenzaldehyde in Step A and 1-benzyl-2,5-dihydro-1H-pyrroleinstead of 1-benzyl-3-methyl-2,5-dihydro-1H-pyrrole (Intermediate 9) inStep B. MS (ESI): mass calcd. for C₂₀HnF₃N₂O₃, 394.2; m/z found, 395.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.54-7.49 (m, 1H), 7.25-7.19 (m, 2H),6.06 (br s, 1H), 4.38 (s, 2H), 4.07-4.02 (m, 1H), 3.76-3.68 (m, 2H),3.65-3.59 (m, 1H), 2.96-2.87 (m, 1H), 2.70-2.60 (m, 2H), 2.56-2.47 (m,5H), 1.99-1.88 (m, 2H), 1.71-1.67 (m, 1H).

Example 114:(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-1-Methyl-6-(4-methyl-3-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A:N′-(4-Bromo-3-(trifluoromethoxy)benzylidene)-4-methylbenzenesulfonohydrazide.4-Methylbenzenesulfonohydrazide (1.7 g, 9.29 mmol) was added to asolution of 4-bromo-3-(trifluoromethoxy)benzaldehyde (2.5 g, 9.29 mmol)in MeOH (50 mL). The reaction mixture was stirred for 16 hours at roomtemperature and then cooled to −10° C. The precipitate was collected byfiltration and washed with cold MeOH before drying under reducedpressure to afford the title compound as a white solid (3.2 g, 78%yield), which was carried on without further purification. ¹H NMR (400MHz, DMSO-d₆) δ 11.75 (br s, 1H), 7.92 (s, 1H), 7.86-7.81 (m, 1H),7.79-7.72 (m, 2H), 7.66 (s, 1H), 7.57-7.50 (m, 1H), 7.43-7.36 (m, 2H),2.36 (s, 3H).

Step B:(rac)-(1*R,5*S,6*R)-3-Benzyl-6-(4-bromo-3-(trifluoromethoxy)phenyl)-1-methyl-3-azabicyclo[3.1.0]hexane.Benzyltriethylammonium chloride (156 mg, 0.685 mmol) was added to amixture ofN′-(4-bromo-3-(trifluoromethoxy)benzylidene)-4-methylbenzenesulfonohydrazide(1.0 g, 2.30 mmol) in aq. NaOH (15%, 8 mL) and toluene (8 mL). Thereaction mixture was stirred vigorously at 80° C. for 1 hour beforecooling to room temperature. The toluene layer was separated, washedwith sat. aq. NH₄Cl and brine, dried over anhydrous Na₂SO₄, and filteredto obtain 1-bromo-4-(diazomethyl)-2-(trifluoromethoxy)benzene (8 mL intoluene, crude). This was added dropwise over 30 minutes to a −10° C.mixture of 1-benzyl-3-methyl-2,5-dihydro-1H-pyrrole (Intermediate 9, 400mg, 2.31 mmol) and ZnI₂ (737 mg, 2.31 mmol) in DCM (30 mL). The reactionmixture was stirred room temperature for 16 hours before being quenchedwith water and extracted with DCM. The combined organic extracts weredried over anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure to give the crude product, which was purified by FCC (0-13%EtOAc in ether) to afford the title compound as a yellow oil (187 mg,16% yield). MS (ESI): mass calcd. for C₂₀H₁₉BrF₃NO, 425.1; m/z found,425.9 [M+H]⁺.

Step C:(rac)-(1*R,5*S,6*R)-3-Benzyl-1-methyl-6-(4-methyl-3-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane.(rac)-(1*R,5*S,6*R)-3-Benzyl-6-(4-bromo-3-(trifluoromethoxy)phenyl)-1-methyl-3-azabicyclo[3.1.0]hexane(167 mg, 0.392 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (148mg, 1.18 mmol), and Cs₂CO₃ (383 mg, 1.18 mmol) were taken up in H₂O (2mL) and 1,4-dioxane (8 mL). The mixture was sparged with Na for 5minutes and then treated with Pd(dppf)Cl₂.CH₂Cl₂ (32 mg, 0.039 mmol).The resultant mixture was sparged with N₂ for 5 minutes and then stirredwhile heating under microwave irradiation at 120° C. for 1 hour beforecooling to room temperature. The reaction mixture was concentrated underreduced pressure and purified by FCC (0-13% EtOAc in ether) to affordthe title compound as a yellow oil (120 mg, 85% yield). MS (ESI): masscalcd. for C₂₁H₂₂F₃NO, 361.2; m/z found, 362.1 [M+H]⁺.

Step D:(rac)-(1*R,5*S,6*R)-1-Methyl-6-(4-methyl-3-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane.(rac)-(1*R,5*S,6*R)-3-Benzyl-1-methyl-6-(4-methyl-3-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane(100 mg, 0.277 mmol) and dry Pd/C (100 mg, 10 wt. %) were taken up inMeOH (2 mL) and THF (10 mL). The resultant mixture was stirred under H₂(15 psi) at room temperature for 1 hour. The suspension was filteredthrough a pad of Celite® and the pad washed with MeOH. The filtrate wasconcentrated under reduced pressure to afford the title product as ayellow oil (90 mg, quant.), which was used in the next step withoutfurther purification. MS (ESI): mass calcd. for C₁₄H₁₆F₃NO, 271.1; m/zfound, 272.1 [M+H]⁺.

Step E:(rac)-(2s,4*S)-2-(1*R,5*S,6*R)-1-Methyl-6-(4-methyl-3-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.T₃P® (0.30 mL, 50% in ethyl acetate, 0.50 mmol) was added to a solutionof(rac)-(1*R,5*S,6*R)-1-methyl-6-(4-methyl-3-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane(90 mg, 0.33 mmol),(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 56 mg, 0.33 mmol), and DIPEA (0.29 mL, 1.6 mmol) in DCM(10 mL). The reaction was stirred at room temperature for 16 hoursbefore being quenched with H₂O and extracted with DCM. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to give the crude product, which waspurified by RP-HPLC (40-70% (v/v) CH₃CN in H₂O with 0.05% NH₃+10 mMNH₄HCO₃) to afford the title compound as a pale solid (23 mg, 16%yield). MS (ESI): mass calcd. for C₂₁H₂₃F₃N₂O₄, 424.2; m/z found, 425.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.17 (d, J=8.0 Hz, 1H), 6.99-6.92 (m,2H), 6.00-5.91 (m, 1H), 4.36 (d, J=5.6 Hz, 2H), 4.06-3.94 (m, 1H),3.75-3.57 (m, 2H), 3.48-3.32 (m, 1H), 2.94-2.83 (m, 1H), 2.69-2.57 (m,2H), 2.56-2.45 (m, 2H), 2.29 (s, 3H), 1.83-1.79 (m, 2H), 1.05 (s, 3H).

Example 115:(2s,4S)-2-((1R,5S,6S)-6-(4-Methyl-3-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 114using 1-benzyl-2,5-dihydro-1H-pyrrole instead of1-benzyl-3-methyl-2,5-dihydro-1H-pyrrole (Intermediate 9) in Step B. MS(ESI): mass calcd. for C₂₀H₂₁F₃N₂O₄, 410.1; m/z found, 411.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.18-7.10 (m, 1H), 6.90-6.80 (m, 2H), 6.15 (br s,1H), 4.40-4.32 (m, 2H), 4.03-3.94 (m, 1H), 3.71-3.62 (m, 2H), 3.60-3.52(m, 1H), 2.94-2.82 (m, 1H), 2.70-2.58 (m, 2H), 2.55-2.43 (m, 2H),2.30-2.23 (m, 3H), 1.93-1.84 (m, 2H), 1.63-1.61 (m, 1H).

Example 116:(2s,4S)-2-((1R,5S,6R)-6-(6-(tert-Butyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: tert-Butyl(1R,5S,6s)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate.TMEDA (1.42 mL, 9.47 mmol) was added to a solution of CrCl₂ (1.16 g,9.44 mmol) in THF (30 mL). The resultant blue mixture was stirred atroom temperature for 15 mins. tert-Butyl2,5-dihydro-1H-pyrrole-1-carboxylate (200 mg, 1.18 mmol) in THF (10 mL)was added followed by a solution of2-(dichloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg, 2.37mmol) and LiI (633 mg, 4.73 mmol) in THF (15 mL). The mixture wasstirred at room temperature for 16 hours before being quenched withwater and extracted with ethyl acetate. The combined organic layers weredried over Na₂SO₄, filtered, and concentrated under reduced pressure toafford the crude product, which was purified by FCC (0-5% EtOAc inether) to give the product as colorless oil (300 mg, 82% yield). ¹H NMR(400 MHz, CDCl₃) δ 3.65-3.49 (m, 2H), 3.39-3.28 (m, 2H), 1.72-1.63 (m,2H), 1.45-1.39 (m, 9H), 1.22 (s, 12H), 0.15-0.29 (m, 1H).

Step B: tert-Butyl(1R,5S,6r)-6-(6-(tert-butyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate.tert-Butyl(1R,5S,6s)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(200 mg, 0.647 mmol), 2-bromo-6-(tert-butyl)pyridine (166 mg, 0.775mmol), and Cs₂CO₃ (632 mg, 1.94 mmol) were taken up in2-methyl-2-butanol (4 mL) and H₂O (1 mL). The resultant mixture wassparged with N₂ for 5 minutes and then treated with CataCXium A Pd G₃(24 mg, 0.033 mmol). The mixture was sparged with N₂ for another 5minutes and then stirred at 90° C. for 1 hour under microwaveirradiation before cooling to room temperature. The reaction mixture wasquenched with water and extracted with DCM. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentratedunder reduced pressure to afford the crude product, which was purifiedby FCC (0-13% EtOAc in ether) to afford the title compound as a yellowoil (300 mg, quant.). MS (ESI): mass calcd. for C₁₉H₂₈N₂O₂, 316.2; m/zfound, 317.2 [M+H]⁺.

Step C:(1R,5S,6r)-6-(6-(tert-Butyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane.tert-Butyl(1R,5S,6r)-6-(6-(tert-butyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(300 mg, 0.948 mmol) and TFA (3 mL, 17.7 mmol) in DCM (6 mL) was stirredat room temperature for 30 minutes. The reaction mixture wasconcentrated under reduced pressure to afford the title compound as ayellow oil (350 mg, crude), which was used in the next step withoutfurther purification. MS (ESI): mass calcd. for C₁₄H₂₀N₂, 216.2; m/zfound, 217.2 [M+H]⁺.

Step D:(2s,4S)-2-((1R,5S,6R)-6-(6-(tert-Butyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.T3P® (0.83 mL, 50% in ethyl acetate, 1.40 mmol) was added to a solutionof 6-(6-(tert-butyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane (350 mg,crude, 1.62 mmol),(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 160 mg, 0.935 mmol), and DIPEA (0.83 mL, 4.70 mmol) inDCM (10 mL). The reaction was stirred at room temperature for 16 hoursbefore being quenched with H₂O and extracted with DCM. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to afford the crude product, whichwas purified by RP-HPLC (38-68% (v/v) CH₃CN in H₂O with 0.05% NH₃+10 mMNR₄CO₃) to afford the title compound as a white solid (45 mg, 13%yield). MS (ESI): mass calcd. for C₂₁H₂₇N₃O₃, 369.2; m/z found, 370.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.50-7.44 (m, 1H), 7.09 (d, J=7.7 Hz,1H), 6.93 (d, J=7.5 Hz, 1H), 5.94 (br s, 1H), 4.37 (s, 2H), 3.97 (d,J=12.3 Hz, 1H), 3.71-3.63 (m, 2H), 3.58 (dd, J=4.3, 12.3 Hz, 1H),2.95-2.86 (m, 1H), 2.68-2.60 (m, 2H), 2.57-2.46 (m, 2H), 2.28-2.18 (m,2H), 1.73 (t, J=3.2 Hz, 1H), 1.30 (s, 9H).

Example 117:(2s,4*R)-2-((1*S,6*R)-6-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 58 (Stationary phase: OJ-H, 2×25 cm, Mobilephase: 15% EtOH, 85% CO₂). MS (ESI): mass calcd. for C₂₀H₂₁F₃N₂O₃,394.2; m/z found, 395.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.59-7.51 (m,2H), 7.37-7.29 (m, 2H), 6.03 (d, J=19.4 Hz, 1H), 4.38 (d, J=10.1 Hz,2H), 4.01-3.90 (m, 1H), 3.87-3.66 (m, 1H), 3.59-3.43 (m, 1H), 3.40-3.21(m, 1H), 3.06-2.91 (m, 1H), 2.72-2.60 (m, 2H), 2.54-2.44 (m, 2H),2.23-2.07 (m, 2H), 1.58-1.42 (m, 1H), 1.09 (dt, J=9.0, 5.3 Hz, 1H), 0.87(q, J=5.3 Hz, 1H).

Example 118:(2s,4*5)-2-((1*R,6*S)-6-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 58 (Stationary phase: OJ-H, 2×25 cm, Mobilephase: 15% EtOH, 85% CO₂). MS (ESI): mass calcd. for C₂₀H₂₁F₃N₂O₃,394.2; m/z found, 395.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.55 (d, J=8.1Hz, 2H), 7.36-7.30 (m, 2H), 6.30 (d, J=14.6 Hz, 1H), 4.38 (d, J=10.0 Hz,2H), 4.00-3.91 (m, 1H), 3.87-3.66 (m, 1H), 3.58-3.42 (m, 1H), 3.41-3.23(m, 1H), 3.06-2.91 (m, 1H), 2.73-2.63 (m, 2H), 2.52-2.41 (m, 2H),2.22-2.07 (m, 2H), 1.58-1.41 (m, 1H), 1.12-1.04 (m, 1H), 0.86 (q, J=5.3Hz, 1H).

Example 119:(2r,4*5)-2-((1*R,6*5)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 52 (Stationary phase: CHIRALPAK AD-H, 5 μm250×21.2 mm, Mobile phase: 22% EtOH, 78% CO₂). MS (ESI): mass calcd. forC₂₁H₂₃F₃N₂O₃, 408.2; m/z found, 409.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.34-7.28 (m, 1H), 7.20-7.11 (m, 1H), 7.10-7.02 (m, 2H), 5.95 (d, J=12.1Hz, 1H), 3.94 (d, J=3.8 Hz, 1H), 3.85-3.65 (m, 1H), 3.58-3.21 (m, 2H),3.00 (dt, J=17.7, 8.4 Hz, 1H), 2.60-2.47 (m, 2H), 2.45-2.32 (m, 4H),2.28-2.17 (m, 2H), 2.17-2.05 (m, 2H), 1.54-1.39 (m, 1H), 1.06 (dt,J=9.1, 5.7 Hz, 1H), 0.84 (q, J=5.3 Hz, 1H).

Example 120:(2r,4*R)-2-((1*S,6*R)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 52 (Stationary phase: CHIRALPAK AD-H, 5 μm250×21.2 mm, Mobile phase: 22% EtOH, 78% CO₂). MS (ESI): mass calcd. forC₂₁H₂₃F₃N₂O₃, 408.2; m/z found, 409.2 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 7.34-7.28 (m, 1H), 7.18-7.13 (m, 1H), 7.10-7.02 (m, 2H),5.95 (d, J=11.9 Hz, 1H), 3.94 (d, J=3.7 Hz, 1H), 3.85-3.65 (m, 1H),3.58-3.20 (m, 2H), 3.00 (dt, J=17.8, 8.4 Hz, 1H), 2.60-2.47 (m, 2H),2.44-2.32 (m, 4H), 2.26-2.17 (m, 2H), 2.17-2.04 (m, 2H), 1.53-1.38 (m,1H), 1.06 (dt, J=9.1, 5.6 Hz, 1H), 0.83 (q, J=5.3 Hz, 1H).

Example 121:(2r,4*5)-2-((1*R,6*S)-6-(4-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 55 (Stationary phase: CHIRALPAK AD-H, 5 μm250×30 mm, Mobile phase: 50% MeOH, 50% CO₂). MS (ESI): mass calcd. forC₂₁H₂₃F₃N₂O₃, 408.2; m/z found, 409.2 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 7.26-7.21 (m, 2H), 7.16-7.10 (m, 2H), 6.17-6.05 (m, 1H),4.00-3.86 (m, 1H), 3.86-3.65 (m, 1H), 3.58-3.39 (m, 1H), 3.40-3.19 (m,1H), 3.00 (dt, J=18.3, 8.5 Hz, 1H), 2.60-2.48 (m, 2H), 2.44-2.31 (m,4H), 2.27-2.17 (m, 2H), 2.11 (tt, J=7.6, 4.7 Hz, 2H), 1.50-1.36 (m, 1H),1.07-0.99 (m, 1H), 0.81 (td, J=5.4, 3.2 Hz, 1H).

Example 122:(2r,4*R)-2-((1*S,6*R)-6-(4-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared by chiral supercritical fluidchromatography of Example 55 (Stationary phase: CHIRALPAK AD-H, 5 μm250×30 mm, Mobile phase: 50% MeOH, 50% CO₂). MS (ESI): mass calcd. forC₂₁H₂₃F₃N₂O₃, 408.2; m/z found, 409.2 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 7.26-7.20 (m, 2H), 7.17-7.10 (m, 2H), 6.04 (d, J=11.0Hz, 1H), 4.01-3.86 (m, 1H), 3.85-3.64 (m, 1H), 3.57-3.40 (m, 1H),3.40-3.19 (m, 1H), 3.00 (dt, J=18.3, 8.4 Hz, 1H), 2.61-2.47 (m, 2H),2.44-2.30 (m, 4H), 2.27-2.19 (m, 2H), 2.11 (tt, J=8.3, 5.4 Hz, 2H),1.50-1.36 (m, 1H), 1.03 (dt, J=9.2, 4.8 Hz, 1H), 0.81 (td, J=5.4, 3.2Hz, 1H).

Example 123:(rac)-(2s,4s)-2-(7-Chloro-6-phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 1 using7-chloro-6-phenyl-3-azabicyclo[4.1.0]heptane instead of1-(p-tolyl)-3-azabicyclo[3.1.0]hexane. MS (ESI): mass calcd. forC₁₉H₂₁ClN₂O₃, 360.1; m/z found, 361.1 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 7.41-7.32 (m, 2H), 7.32-7.21 (m, 3H), 5.92 (d, J=15.4Hz, 1H), 4.38 (d, J=20.2 Hz, 2H), 4.17-3.77 (m, 2H), 3.75-3.12 (m, 2H),3.10-2.86 (m, 2H), 2.72-2.60 (m, 2H), 2.58-2.41 (m, 2H), 2.23-2.06 (m,2H), 1.93-1.81 (m, 1H).

Example 124:(rac)-(2s,4s)-2-(7,7-Dichloro-6-phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 1 using7,7-dichloro-6-phenyl-3-azabicyclo[4.1.0]heptane instead of1-(p-tolyl)-3-azabicyclo[3.1.0]hexane. MS (ESI): mass calcd. forC₁₉H₂₀Cl₂N₂O₃, 394.1; m/z found, 395.0 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 7.43-7.33 (m, 2H), 7.34-7.28 (m, 1H), 7.26-7.21 (m, 2H),5.95 (d, J=16.4 Hz, 1H), 4.38 (d, J=25.5 Hz, 2H), 4.27-3.39 (m, 3H),3.15-3.03 (m, 1H), 2.95-2.50 (m, 4H), 2.50-2.31 (m, 2H), 2.25-2.08 (m,2H).

Biological Data

The assay used to measure the in vitro activity of MGL is adapted fromthe assay used for another serine hydrolase (FAAH) described in Wilsonet al., 2003 (A high-throughput-compatible assay for determining theactivity of fatty acid amide hydrolase. Wilson S J, Lovenberg T W,Barbier A J. Anal Biochem. 2003 Jul. 15; 318(2):270-5). The assayconsists of combining endogenously expressed MGL from HeLa cells withtest compounds, adding[glycerol-1,3-³H]-oleoyl glycerol, incubating forone hour, and then measuring the amount of cleaved[1,3-³H]-glycerol thatpasses through an activated carbon filter. The amount of cleaved,tritiated glycerol passing through the carbon filter is proportional tothe activity of the MGL enzyme in a particular well/test condition.

Standard conditions for this assay combine 300 nM[Glycerol-1,3-³H]-oleoyl glycerol with human MGL from HeLa cells andtest compounds for one hour, after which the reaction is filteredthrough activated carbon and tritium is measured in the flow through.The test compound concentration in screening mode is 10 μM, while thehighest compound concentration in IC₅₀ assays is determined empirically.MGL is the predominant hydrolase in HeLa cells/cell homogenates.

TABLE 3 MGL IC₅₀ Ex # Compound Name (nM) 1(rac)-(2s,4s)-2-(1-(p-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-5.9 oxa-5-azaspiro[3.4]octan-6-one; 2(2s,4*R)-2-((1*S,5*R)-1-(p-Tolyl)-3-azabicyclo[3.1.0]hexane-3- 17carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 3(2s,4*S)-2-((1*R,5*S)-1-(p-Tolyl)-3-azabicyclo[3.1.0]hexane-3- 8.5carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 4(rac)-(2s,4s)-2-(1-Phenyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-49 5-azaspiro[3.4]octan-6-one; 5(rac)-(2s,4s)-2-(1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-1.4 carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 6(rac)-(2s,4s)-2-(1-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3- 6.9carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 7(2s,4*S)-2-((1*R,5*S)-1-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-5.0 3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 8(2s,4*R)-2-((1*S,5*R)-1-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-11 3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 9(rac)-(2s,4s)-2-(1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3- 2.2carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 10(2s,4*S)-2-((1*R,5*S)-1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-2.3 3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 11(2s,4*R)-2-((1*S,5*R)-1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-2.3 3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 12(rac)-(2r,4s)-2-(1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3- 14carbonyl)-5-azaspiro[3.4]octan-6-one; 13(rac)-(2r,4s)-2-(1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-9.2 carbonyl)-5-azaspiro[3.4]octan-6-one; 14(2r,4*S)-2-((1*R,5*S)-1-(4-(tert-Butyl)phenyl)-3- 23azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 15(2r,4*R)-2-((1*S,5*R)-1-(4-(tert-Butyl)phenyl)-3- 12azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 16(rac)-(2s,4s)-2-(1-(3-Cyclopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-5.6 carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 17(rac)-(2s,4s)-2-(1-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-3.8 carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 18(rac)-(2s,4s)-2-(1-(4-Cyclopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-4.4 carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 19(rac)-(2s,4s)-2-(1-(3-(Trifluoromethoxy)phenyl)-3- 11azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 20(rac)-(2s,4s)-2-(1-(o-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-6.5 oxa-5-azaspiro[3.4]octan-6-one; 21(rac)-(2s,4s)-2-(1-(m-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7- 14oxa-5-azaspiro[3.4]octan-6-one; 22(rac)-(2s,4s)-2-(1-(4-(Trifluoromethoxy)phenyl)-3- 16azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 23(rac)-(2s,4s)-2-(1-(3-(Trifluoromethyl)phenyl)-3- 14azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 24(rac)-(2s,4s)-2-(1-(4-(Trifluoromethyl)phenyl)-3- 15azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 25(rac)-(2s,4s)-2-(1-(4-Methyl-3-(trifluoromethyl)phenyl)-3- 3.6azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 26(rac)-(2s,4s)-2-(1-(4-(1-Methylcyclopropyl)phenyl)-3- 1.4azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 27(rac)-(2r,4s)-2-(1-(4-(1-Methylcyclopropyl)phenyl)-3- 9.5azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 28(rac)-(2s,4s)-2-(1-(4-Phenoxyphenyl)-3-azabicyclo[3.1.0]hexane-3- 1.7carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 29(rac)-(2s,4s)-2-(1-(3-Phenoxyphenyl)-3-azabicyclo[3.1.0]hexane-3- 1.5carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 30(rac)-(2s,4s)-2-(1-(3-Chloro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane-2.9 3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 31(rac)-(2s,4s)-2-(1-(3-(1-Methylcyclopropyl)phenyl)-3- 1.1azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 32(rac)-(2s,4s)-2-(1-(4-Cyclopropy1-2-methylphenyl)-3- 0.35azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 33(rac)-(2s,4s)-2-(1-(2-Methyl-4-(trifluoromethyl)phenyl)-3- 2.5azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 34(rac)-(2s,4s)-2-(1-(2-Methyl-4-(trifluoromethoxy)phenyl)-3- 3.1azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 35(rac)-(2s,4s)-2-(1-(3-Methyl-4-(trifluoromethoxy)phenyl)-3- 6.5azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 36(rac)-(2s,4s)-2-(1-(3-Methyl-4-(trifluoromethyl)phenyl)-3- 3.2azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 37(rac)-(2s,4s)-2-(1-(3-Fluoro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane-10 3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 38(2s,4S)-2-((1R,5S,6S)-6-(3-(Trifluoromethoxy)phenyl)-3- 21azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 39(rac)-(2s,4s)-2-(6-Phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-20 5-azaspiro[3.4]octan-6-one; 40(2s,4S)-2-((1R,6S)-6-Phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-136 oxa-5-azaspiro[3.4]octan-6-one; 41(2s,4R)-2-((1S,6R)-6-Phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-9.6 oxa-5-azaspiro[3.4]octan-6-one; 42(rac)-(2s,4s)-2-(7,7-Difluoro-6-phenyl-3-azabicyclo[4.1.0]heptane-3- 203carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 43(rac)-(2s,4s)-2-(6-(m-Tolyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-8.2 oxa-5-azaspiro[3.4]octan-6-one; 44(2s,4*R)-2-((1*S,6*R)-6-(m-Tolyl)-3-azabicyclo[4.1.0]heptane-3- 2.8carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 45(2s,4*S)-2-((1*R,6*S)-6-(m-Tolyl)-3-azabicyclo[4.1.0]heptane-3- 32carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 46(rac)-(2s,4s)-2-(6-(3-Fluoro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3.7 3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 47(2s,4*R)-2-((1*S,6*R)-6-(3-Fluoro-4-methylphenyl)-3- 21azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;48 (2s,4*S)-2-((1*R,6*S)-6-(3-Fluoro-4-methylphenyl)-3- 1.3azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;49 (rac)-(2s,4s)-2-(6-(3-(Trifluoromethoxy)phenyl)-3- 1.6azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;50 (2s,4*R)-2-((1*S,6*R)-6-(3-(Trifluoromethoxy)phenyl)-3- 4.2azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;51 (2s,4*S)-2-((l*R,6*S)-6-(3-(Trifluoromethoxy)phenyl)-3- 0.52azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;52 (rac)-(2r,4s)-2-(6-(3-(Trifluoromethoxy)phenyl)-3- 4.8azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 53(rac)-(2s,4s)-2-(6-(o-Tolyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-51 oxa-5-azaspiro[3.4]octan-6-one; 54(rac)-(2s,4s)-2-(6-(4-(Trifluoromethoxy)phenyl)-3- 2.5azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;55 (rac)-(2r,4s)-2-(6-(4-(Trifluoromethoxy)phenyl)-3- 10azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 56(rac)-(2s,4s)-2-(6-(p-Tolyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-7.7 oxa-5-azaspiro[3.4]octan-6-one; 57(rac)-(2s,4s)-2-(6-(3-(Trifluoromethyl)phenyl)-3- 1.9azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;58 (rac)-(2s,4s)-2-(6-(4-(Trifluoromethyl)phenyl)-3- 1.4azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;59 (rac)-(2r,4s)-2-(6-(4-(Trifluoromethyl)phenyl)-3- 18azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 60(rac)-(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-0.0072 carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 61(rac)-(2r,4s)-2-(6-(3-(tert-Butyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-0.25 carbonyl)-5-azaspiro[3.4]octan-6-one; 62(rac)-(2s,4s)-2-(6-(4-(tert-Butyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-0.019 carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 63(rac)-(2r,4s)-2-(6-(4-(tert-Butyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-0.41 carbonyl)-5-azaspiro[3.4]octan-6-one; 64(rac)-(2s,4s)-2-(6-(3-Cyclopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-0.65 carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 65(rac)-(2r,4s)-2-(6-(3-Cyclopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-4.0 carbonyl)-5-azaspiro[3.4]octan-6-one; 66(rac)-(2s,4s)-2-(6-(4-Cyclopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-0.69 carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 67(rac)-(2s,4s)-2-(6-(3-Chloro-4-methylphenyl)-3- 0.075azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;68(rac)-(2r,4s)-2-(6-(3-Chloro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-5.6 3-carbonyl)-5-azaspiro[3.4]octan-6-one; 69(rac)-(2s,4s)-2-(6-(4-(1-Methylcyclopropyl)phenyl)-3- 0.034azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;70 (rac)-(2r,4s)-2-(6-(4-(1-Methylcyclopropyl)phenyl)-3- 0.52azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 71(rac)-(2s,4s)-2-(6-(3-(1-Methylcyclopropyl)phenyl)-3- 0.024azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;72 (rac)-(2s,4s)-2-(6-(4-Cyclopropy1-2-methylphenyl)-3- 2.1azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;73 (rac)-(2s,4s)-2-(6-(3-Isopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-0.25 carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 74(rac)-(2s,4s)-2-(6-(4-Isopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-0.21 carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 75(rac)-(2s,4s)-2-(6-(4-Methyl-3-(trifluoromethoxy)phenyl)-3- 0.34azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;76 (rac)-(2r,4s)-2-(6-(4-Methyl-3-(trifluoromethoxy)phenyl)-3- 2.6azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 77(rac)-(2s,4s)-2-(1-Phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-241 5-azaspiro[3.4]octan-6-one; 78(2s,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl)-3- 0.99azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 79(2r,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl)-3- 7.2azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 80(2s,4S)-2-((1R,5S,6S)-6-(4-(Trifluoromethyl)phenyl)-3- 33azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 81(2r,4S)-2-((1R,5S,6S)-6-(4-(Trifluoromethyl)phenyl)-3- 206azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 82(2s,4S)-2-((1R,5S,6S)-6-(4-(tert-Butyl)phenyl)-3- 0.69azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 83(2r,4S)-2-((1R,5S,6S)-6-(4-(tert-Butyl)phenyl)-3- 2.9azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 84(2s,4S)-2-((1R,5S,6S)-6-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-5.5 3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 85(2s,4S)-2-((1R,5S,6S)-6-(4-Methyl-3-(trifluoromethyl)phenyl)-3- 4.4azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 86(2s,4S)-2-((1R,5S,6S)-6-(4-Ethylphenyl)-3-azabicyclo[3.1.0]hexane-3- 25carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 87(2r,4S)-2-((1R,5S,6S)-6-(4-Ethylphenyl)-3-azabicyclo[3.1.0]hexane-3- 131carbonyl)-5-azaspiro[3.4]octan-6-one; 88(2s,4S)-2-((1R,5S,6S)-6-(3,4-Dimethylphenyl)-3- 29azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 89(2r,4S)-2-((1R,5S,6S)-6-(3,4-Dimethylphenyl)-3- 178azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 90(2s,4S)-2-((1R,5S,6S)-6-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-2.8 3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 91(2r,4S)-2-((1R,5S,6S)-6-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-20 3-carbonyl)-5-azaspiro[3.4]octan-6-one; 92(2s,4S)-2-((1R,5S,6S)-6-(2,3-Dihydro-lH-inden-5-yl)-3- 4.7azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 93(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-6-(3-(tert-Butyl)phenyl)-1-methyl-3-0.76azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 94(rac)-(2s,4s)-2-(1-(4-Ethylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-3.5 7-oxa-5-azaspiro[3.4]octan-6-one; 95 (2r,4*S)-2-((1*R,5*S)-1-(4-(1-Methylcyclopropyl)phenyl)-3- 7.5azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 96(2r,4*R)-2-((1*S,5*R)-1-(4-(1-Methylcyclopropyl)phenyl)-3- 8.5azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 97(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-1-Methyl-6-(o-tolyl)-3- 180azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 98(2s,4S)-2-((1R,5S,6S)-6-(o-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-150 7-oxa-5-azaspiro[3.4]octan-6-one; 99 (2s,4*S)-2-((1*R,5*S,6*R)-6-(3-(tert-Butyl)phenyl)-1-methyl-3- 0.64azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;100 (2s,4*R)-2-((1*S,5*R,6*S)-6-(3-(tert-Butyl)phenyl)-1-methyl-3- 8.3azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;101(2s,4S)-2-((1R,5S,6S)-6-(3-Isobutylphenyl)-3-azabicyclo[3.1.0]hexane-3-1.5 carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 102(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-6-(3,4-Dimethylphenyl)-1-methyl-3- 23azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;103 (2s,4S)-2-((1R,5S, 6S)-6-(3-(ter1-Butyl)phenyl-5-D)-3- 0.93azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;104 (2s,4S)-2-((1R,5S,6S)-6-(3-(1-Hydroxy-2-methylpropan-2-yl)phenyl)-3-19 azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;1052-Methyl-2-(3-((1R,5S,6S)-3-((2s,4S)-6-oxo-7-oxa-5-azaspiro[3.4]octane-300 2-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)phenyl)propanoic acid; 106(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-1-Methyl-6-(3-(trifluoromethyl)phenyl)-283-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;107 (rac)-(2s,4*S)-2-((1*R, 5*S,6*R)-1-Methyl-6-(4- 73(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4] octan-6-one; 108(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-6-(4-Cyclopropylphenyl)-1-methyl-3- 38azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;109 (2s,4S)-2-((1R,5S,6S)-6-(4-Cyclopropy1-2-methylphenyl)-3- 1.6azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;110 (2s,4S)-2-((1R,5S,6S)-6-(3-Chloro-4-methylphenyl)-3- 17azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;111 (2s,4S)-2-((1R,5S, 6S)-6-(3-Ethy1-4-fluorophenyl)-3- 11azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;112 (rac)-(2s,4*S)-2-((1*R, 5*S,6*R)-1-Methyl-6-(4-methyl-3- 6.0(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro 3.4] octan-6-one; 113(2s,4S)-2-((1R,5S,6S)-6-(2-Methyl-3-(trifluoromethyl)phenyl)-3- 78azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;114 (rac)-(2s,4*S)-2-((1*R, 5*S,6*R)-1-Methyl-6-(4-methyl-3- 4.1(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4] octan-6-one; 115(2s,4S)-2-((1R,5S,6S)-6-(4-Methyl-3-(trifluoromethoxy)phenyl)-3- 5.2azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;116 (2s,4S)-2-((1R,5S,6R)-6-(6-(tert-Butyl)pyridin-2-yl)-3- 5.2azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;117 (2s,4*R)-2-((1*S,6*R)-6-(4-(Trifluoromethyl)phenyl)-3- 22azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;118 (2s,4*S)-2-((1*R,6*S)-6-(4-(Trifluoromethyl)phenyl)-3- 1.6azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;119 (2r,4*S)-2-((1*R,6*S)-6-(3-(Trifluoromethoxy)phenyl)-3- 5.2azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 120(2r,4*R)-2-((1*5,6*R)-6-(3-(Trifluoromethoxy)phenyl)-3- 23azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 121(2r,4*S)-2-((1*R,6*5)-6-(4-(Trifluoromethoxy)phenyl)-3- 42azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 122(2r,4*R)-2-((1*S,6*S)-6-(4-(Trifluoromethoxy)phenyl)-3- 12azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one; 123(rac)-(25,45)-2-(7-Chloro-6-phenyl-3-azabicyclo[4.1.0]heptane-3- 200carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; and 124(rac)-(2s,4s)-2-(7,7-Dichloro-6-phenyl-3-azabicyclo[4.1.0]heptane-3- 32carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one. NT means not tested

What is claimed:
 1. A compound of Formula (I),

wherein X is CH₂ or O; Y is selected from the group consisting of:

R¹ is H; R^(2a) and R^(2b) are each independently H; R³ is selected fromthe group consisting of: 2,3-dihydro-1H-indene; pyridyl substituted withC₁₋₆alkyl; phenyl; and phenyl substituted with one or two members eachindependently selected from the group consisting of: halo, C₁₋₆alkyl,C₁₋₆alkyl substituted with OH, C₁₋₆alkyl substituted with CO₂H,C₁₋₆haloalkyl, OC₁₋₆haloalkyl, C₃₋₆cycloalkyl, O-phenyl, andC₃₋₆cycloalkyl substituted with CH₃; R^(a) and R^(b) are eachindependently selected from the group consisting of: H and halo; andR^(c) is H or CH₃; and pharmaceutically acceptable salts, isotopes,N-oxides, solvates, and stereoisomers thereof.
 2. A compound as claimedin claim 1, wherein X is CH₂.
 3. A compound as claimed in claim 1,wherein X is O.
 4. A compound as claimed in claim 1, wherein Y is


5. A compound as claimed in claim 1, wherein Y is


6. A compound as claimed in claim 1, wherein Y is


7. A compound as claimed in claim 1, wherein R^(a) and R^(b) are H.
 8. Acompound as claimed in claim 1, wherein R^(a) and R^(b) are eachindependently selected from the group consisting of: H and Cl.
 9. Acompound as claimed in claim 1, wherein R^(a) and R^(b) are F.
 10. Acompound as claimed in claim 1, wherein R³ is


11. A compound as claimed in claim 1, wherein R³ is phenyl, or phenylsubstituted with one or two members each independently selected from thegroup consisting of: Cl, F, CH₃, CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CH₂CH(CH₃)₂,C(CH₃)₂CH₂OH, C(CH₃)₂CH₂CO₂H, CF₃, OCF₃, cyclopropyl, cyclopropylsubstituted with CH₃, and O-phenyl.
 12. A compound as claimed in claim1, wherein R³ is


13. A compound as claimed in claim 1, wherein R³ is 3-tert-butylphenyl,4-tert-butylphenyl, 4-methyl-3-trifluoromethylphenyl, or3,4-dimethylphenyl.
 14. A compound as claimed in claim 1, selected fromthe group consisting of:(rac)-(25,45)-2-(1-(p-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxaazaspiro[3.4]octan-6-one;(2s,4*R)-2-((1*S,5*R)-1-(p-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxaazaspiro[3.4]octan-6-one;(2s,4*S)-2-((1*R,5*S)-1-(p-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(25,45)-2-(1-Phenyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(25,45)-2-(1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4*S)-2-((1*R,5*S)-1-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4*R)-2-((1*S,5*R)-1-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(25,45)-2-(1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4*S)-2-((1*R,5*S)-1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4*R)-2-((1*S,5*R)-1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2r,45)-2-(1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(rac)-(2r,45)-2-(1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)azaspiro[3.4]octan-6-one; (2r,4*S)-2-((1*R,5*S)-1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)azaspiro[3.4]octan-6-one; (2r,4*R)-2-((1*S,5*R)-1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(3-Cyclopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxaazaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(4-Cyclopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(o-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(m-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(4-(Trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(3-(Trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(4-Methyl-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2r,4s)-2-(1-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(4-Phenoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxaazaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(3-Phenoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxaazaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(3-Chloro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(3-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(4-Cyclopropyl-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(2-Methyl-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(2-Methyl-4-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(3-Methyl-4-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(3-Methyl-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(3-Fluoro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S)-2-((1R,5S,6S)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-Phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S)-2-((1R,6S)-6-Phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4R)-2-((1S,6R)-6-Phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxaazaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(7,7-Difluoro-6-phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxaazaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(m-Tolyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxaazaspiro[3.4]octan-6-one;(2s,4*R)-2-((1*S,6*R)-6-(m-Tolyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxaazaspiro[3.4]octan-6-one;(2s,4*S)-2-((1*R,6*S)-6-(m-Tolyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(3-Fluoro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4*R)-2-((1*S,6*R)-6-(3-Fluoro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4*S)-2-((1*R,6*S)-6-(3-Fluoro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4*R)-2-((1*S,6*R)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4*S)-2-((1*R,6*S)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2r,4s)-2-(6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(o-Tolyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(4-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2r,4s)-2-(6-(4-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(p-Tolyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxaazaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(3-(Trifluoromethyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2r,4s)-2-(6-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2r,4s)-2-(6-(3-(tert-Butyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(4-(tert-Butyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2r,4s)-2-(6-(4-(tert-Butyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(3-Cyclopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2r,4s)-2-(6-(3-Cyclopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(4-Cyclopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(3-Chloro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2r,4s)-2-(6-(3-Chloro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[4.1.0]heptanecarbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2r,4s)-2-(6-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[4.1.0]heptanecarbonyl)-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(3-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[4.1.0]heptanecarbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(4-Cyclopropyl-2-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(3-Isopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(4-Isopropylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(4-Methyl-3-(trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2r,4s)-2-(6-(4-Methyl-3-(trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-Phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4S)-2-((1R,5S,6S)-6-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4S)-2-((1R,5S,6S)-6-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4S)-2-((1R,5S,6S)-6-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4S)-2-((1R,5S,6S)-6-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)azaspiro[3.4]octan-6-one; (2s,4 S)-2-((1R,5S,6S)-6-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4 S)-2-((1R,5S,6S)-6-(4-Methyl-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S)-2-((1R,5S,6S)-6-(4-Ethylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxaazaspiro[3.4]octan-6-one; (2r,4 S)-2-((1R,5S,6S)-6-(4-Ethylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4 S)-2-((1R,5S,6S)-6-(3,4-Dimethylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4 S)-2-((1R,5S,6S)-6-(3,4-Dimethylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4 S)-2-((1R,5S,6S)-6-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4 S)-2-((1R,5S,6S)-6-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4 S)-2-((1R,5S,6S)-6-(2,3-Dihydro-1H-inden-5-yl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-6-(3-(tert-Butyl)phenyl)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(1-(4-Ethylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4*S)-2-((1*R,5*S)-1-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4*R)-2-((1*S,5*R)-1-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-1-Methyl-6-(o-tolyl)-3-azabicyclo[3.1.0]hexanecarbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S)-2-((1R,5S,6S)-6-(o-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxaazaspiro[3.4]octan-6-one; (2s,4*S)-2-((1*R,5*S,6*R)-6-(3-(tert-Butyl)phenyl)-1-methyl-3-azabicyclo[3.1.0]hexanecarbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4*R)-2-((1*S,5*R,6*S)-6-(3-(tert-Butyl)phenyl)-1-methyl-3-azabicyclo[3.1.0]hexanecarbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S)-2-((1R,5S,6S)-6-(3-Isobutylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-6-(3,4-Dimethylphenyl)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl-5-D)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S)-2-((1R,5S,6S)-6-(3-(1-Hydroxy-2-methylpropan-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;2-Methyl-2-(3-((1R,5S,6S)-3-((2s,4S)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)phenyl)propanoicacid; (rac)-(2s,4*S)-2-((1*R,5*S,6*R)-1-Methyl-6-(3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-1-Methyl-6-(4-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-6-(4-Cyclopropylphenyl)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S)-2-((1R,5S,6S)-6-(4-Cyclopropyl-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S)-2-((1R,5S,6S)-6-(3-Chloro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S)-2-((1R,5S,6S)-6-(3-Ethyl-4-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-1-Methyl-6-(4-methyl-3-(trifluoromethyl)phenyl)azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S)-2-((1R,5S,6S)-6-(2-Methyl-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexanecarbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4*S)-2-((1*R,5*S,6*R)-1-Methyl-6-(4-methyl-3-(trifluoromethoxy)phenyl)azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S)-2-((1R,5S,6S)-6-(4-Methyl-3-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S)-2-((1R,5S,6R)-6-(6-(tert-Butyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4*R)-2-((1*S,6*R)-6-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4*S)-2-((1*R,6*S)-6-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4*S)-2-((1*R,6*S)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4*R)-2-((1*S,6*R)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4*S)-2-((1*R,6*S)-6-(4-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4*R)-2-((1*S,6*R)-6-(4-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(7-Chloro-6-phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;and(rac)-(2s,4s)-2-(7,7-Dichloro-6-phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-oneand pharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers thereof.
 15. A compound as claimed in claim 1 selectedfrom the group consisting of:(rac)-(2s,4s)-2-(1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxaazaspiro[3.4]octan-6-one;(2s,4*R)-2-((1*S,6*R)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptanecarbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4*S)-2-((1*R,6*S)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;and(2r,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers.
 16. A compound as claimed in claim 14, wherein thecompound is(rac)-(2s,4s)-2-(1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one,and pharmaceutically acceptable salts thereof.
 17. A compound as claimedin claim 14, wherein the compound is(2s,4*R)-2-((1*S,5*R)-1-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one,and pharmaceutically acceptable salts thereof.
 18. A compound as claimedin claim 14, wherein the compound is(2s,4*R)-2-((1*S,6*R)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one,and pharmaceutically acceptable salts thereof.
 19. A compound as claimedin claim 14, wherein the compound is(2s,4*S)-2-((1*R,6*S)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one,and pharmaceutically acceptable salts thereof.
 20. A compound as claimedin claim 14, wherein the compound is (2s,4S)((1R,5S,6S)-6-(3-Chloro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one,and pharmaceutically acceptable salts thereof.
 21. A compound as claimedin claim 14, wherein the compound is(2s,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one,and pharmaceutically acceptable salts thereof.
 22. A compound as claimedin claim 14, wherein the compound is(2s,4*S)-2-((1*R,6*S)-6-(3-Fluoro-4-methylphenyl)-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one,and pharmaceutically acceptable salts thereof.
 23. A compound as claimedin claim 14, wherein the compound is(2r,4S)-2-((1R,5S,6S)-6-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one,and pharmaceutically acceptable salts thereof.
 24. The compound of claim1, and pharmaceutically acceptable salts, isotopes, N-oxides, solvates,and stereoisomers thereof, having the structure of Formula (IA):

wherein X is CH₂ or O; and R³ is selected from the group consisting of:phenyl; phenyl substituted with one or two members each independentlyselected from the group consisting of: halo, C₁₋₆alkyl, C₁₋₆haloalkyl,OC₁₋₆haloalkyl, C₃₋₆cycloalkyl, O-phenyl, and C₃₋₆cycloalkyl substitutedwith CH₃.
 25. The compound of claim 1, and pharmaceutically acceptablesalts, isotopes, N-oxides, solvates, and stereoisomers thereof, havingthe structure of Formula (TB):

wherein X is CH₂ or O; R³ is selected from the group consisting of:2,3-dihydro-1H-indene; pyridyl substituted with C₁₋₆alkyl; phenylsubstituted with one or two members each independently selected from thegroup consisting of: halo, C₁₋₆alkyl, C₁₋₆alkyl substituted with OH,C₁₋₆alkyl substituted with CO₂H, C₁₋₆haloalkyl, OC₁₋₆haloalkyl andcyclopropyl; and R^(c) is H or CH₃.
 26. The compound of claim 1, andpharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers thereof, having the structure of Formula (IC):

wherein X is CH₂ or O; R³ is selected from the group consisting of:phenyl; phenyl substituted with one or two members each independentlyselected from the group consisting of: halo, C₁₋₆alkyl, C₁₋₆haloalkyl,OC₁₋₆haloalkyl, C₃₋₆cycloalkyl, and C₃₋₆cycloalkyl substituted with CH₃;and R^(a) and R^(b) are each independently selected from the groupconsisting of: H, Cl and F.
 27. A pharmaceutical composition comprising:(A) a therapeutically effective amount of at least one compound ofFormula (I):

wherein X is CH₂ or O; Y is selected from the group consisting of:

R¹ is H; R^(2a) and R^(2b) are each independently H; R³ is selected fromthe group consisting of: 2,3-dihydro-1H-indene; pyridyl substituted withC₁₋₆alkyl; phenyl; and phenyl substituted with one or two members eachindependently selected from the group consisting of: halo, C₁₋₆alkyl,C₁₋₆alkyl substituted with OH, C₁₋₆alkyl substituted with CO₂H,C₁₋₆haloalkyl, OC₁₋₆haloalkyl, C₃₋₆cycloalkyl, O-phenyl, andC₃₋₆cycloalkyl substituted with CH₃; R^(a) and R^(b) are eachindependently selected from the group consisting of: H and halo; andR^(c) is H or CH₃; and pharmaceutically acceptable salts, isotopes,N-oxides, solvates, and stereoisomers of compounds of Formula (I); and(B) at least one pharmaceutically acceptable excipient.
 28. Apharmaceutical composition comprising a therapeutically effective amountof at least one compound of claim 14 and at least one pharmaceuticallyacceptable excipient.